TSH-producing Pituitary Adenoma Research Articles

Challenges in the functional diagnosis of thyroid nodules before surgery for TSH-producing pituitary adenoma.

SummaryA 50-year-old woman with thyroid-stimulating hormone (TSH)-producing pituitary adenoma (TSHoma) was diagnosed due to symptoms of thyrotoxicosis. Preoperatively, she showed thyrotoxicosis with the syndrome of inappropriate secretion of TSH (SITSH) and had a 5 cm nodule in her thyroid gland. Octreotide was administered preoperatively, which helped lower her serum TSH level but not her thyroid hormone level. These findings were atypical for a patient with TSHoma. The TSHoma was completely resected, and the TSH level dropped below the sensitivity limit shortly after surgery. Interestingly, however, thyroid hormone levels remained high. A clear clue to the aetiology was provided by consecutive thyroid scintigraphy. Although preoperative thyroid scintigraphy did not show a hot nodule and the mass was thought to be a non-functional thyroid nodule, the nodule was found to be hot in the postoperative phase of TSH suppression. By focusing on the atypical postoperative course of the TSHoma, we were able to conclude that this was a case of TSHoma combined with an autonomously functioning thyroid nodule (AFTN).Learning pointsThe diagnosis of autonomously functioning thyroid nodules (AFTNs) depends on suppressed serum TSH levels.If thyroid hormones are resistant to somatostatin analogue therapy or surgery for TSHoma, complications of AFTN as well as destructive thyroiditis need to be considered.It is important to revisit the basics when facing diagnostic difficulties and not to give up on understanding the pathology.

TSH secreting pituitary tumor — an experience of 20 years follow-up

Thyrotropinoma is a rare pituitary tumor that causes the development of thyrotoxicosis syndrome as a result of hyperproduction of thyroid stimulating hormone (TSH). In the Russian literature over the past 10 years, one case of thyrotropinoma in a child, four cases of TSH-producing pituitary adenoma in women and only one in a man have been described. The article presents a unique clinical case of a 20-years history of observation of a patient with TSH-oma. The rarity of this disease led to the fact that it took more than 10 years to make a correct diagnosis. The first operation of thyroid gland was performed before the diagnosis of pituitary adenoma and inappropriate TSH secretion syndrome. That right hemithyroidectomy was supposed to cure a toxic adenoma of thyroid gland. The diagnosis of thyrotropin-secreting piruitary tumor was established only after 6 years even after finding a combination of pituitary adenoma and thyrotoxicosis. After that, the patient steadfastly refuses neurosurgical treatment, despite the presence of macroadenoma with intrasellar growth. The therapy with somatostatin analogs led to patient’s intolerance with gastrointestinal side effects and hospitalization for acute pancreatitis. The absence of the therapy due to low compliance led to long-term persistence of thyrotoxicosis. The absence of signs and symptoms of expanding tumor mass (visual field defects, loss of vision, headache, partial or total hypopituitarism) demonstrates the slow growth of this kind of pituitary tumor. The long-term effect of elevated TSH levels led to diffuse goiter with compression of the neck organs, and the need of the surgical treatment of the thyroid. Stable euthyroidism after the operation led to stable normoglycemia in the patient with previously diagnosed diabetes mellitus type 2. This fact should keep an attention of physicians and endocrinologists to screen for the secondary reasons of hyperglycemia in a patient with diabetes mellitus manifestation. Long-term history of thyrotoxicosis led to the deleterious effects of thyroid hormone excess on the heart (atrial fibrillation, cardiomyopathy, cardiac failure). Those effects are still observed even after thyroidectomy and medical euthyroidism achievement. This fact demonstrates the importance of early diagnosis and treatment of TSH-omas.

An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.

Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of β type of resistance to thyroid hormone (RTHβ). The differential diagnoses of RTHβ include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHβ, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHβ and TSHoma. The FT3/FT4 values in RTHβ were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.

Тиреотропинома — опыт 20-летнего наблюдения

Thyrotropinoma is a rare pituitary tumor that causes the development of thyrotoxicosis syndrome as a result of hyperproduction of thyroid stimulating hormone (TSH). In the Russian literature over the past 10 years, one case of thyrotropinoma in a child, four cases of TSH-producing pituitary adenoma in women and only one in a man have been described. The article presents a unique clinical case of a 20-years history of observation of a patient with TSH-oma. The rarity of this disease led to the fact that it took more than 10 years to make a correct diagnosis. The first operation of thyroid gland was performed before the diagnosis of pituitary adenoma and inappropriate TSH secretion syndrome. That right hemithyroidectomy was supposed to cure a toxic adenoma of thyroid gland. The diagnosis of thyrotropin-secreting piruitary tumor was established only after 6 years even after finding a combination of pituitary adenoma and thyrotoxicosis. After that, the patient steadfastly refuses neurosurgical treatment, despite the presence of macroadenoma with intrasellar growth. The therapy with somatostatin analogs led to patient’s intolerance with gastrointestinal side effects and hospitalization for acute pancreatitis. The absence of the therapy due to low compliance led to long-term persistence of thyrotoxicosis. The absence of signs and symptoms of expanding tumor mass (visual field defects, loss of vision, headache, partial or total hypopituitarism) demonstrates the slow growth of this kind of pituitary tumor. The long-term effect of elevated TSH levels led to diffuse goiter with compression of the neck organs, and the need of the surgical treatment of the thyroid. Stable euthyroidism after the operation led to stable normoglycemia in the patient with previously diagnosed diabetes mellitus type 2. This fact should keep an attention of physicians and endocrinologists to screen for the secondary reasons of hyperglycemia in a patient with diabetes mellitus manifestation. Long-term history of thyrotoxicosis led to the deleterious effects of thyroid hormone excess on the heart (atrial fibrillation, cardiomyopathy, cardiac failure). Those effects are still observed even after thyroidectomy and medical euthyroidism achievement. This fact demonstrates the importance of early diagnosis and treatment of TSH-omas.

SUN-549 Erratic Medication-Related Malabsorption of L-T4 Associated with Highly Elevated TSH Levels in a Patient with Renal Tubular Acidosis, Thyrotroph Hyperplasia, and Hashimoto's Thyroiditis

Case: A 30-yr-old pregnant woman presented with hypothyroidism at 19 weeks. She had been diagnosed with hypothyroidism 15 years ago and was treated with L-T4. She was told 1-1/2 yr ago that her thyroid levels had normalized and L-T4 was discontinued. Shortly thereafter she became pregnant. Labs then included TSH-37 mU/L (NL: 0.358-3.74) and Free T4 (FT4)-0.52 ng/dL (NL: 0.76-1.46) with elevated Anti-Peroxidase and Anti-Thyroglobulin antibody levels. She was started on L-T4, 25 mcg/d. During the pregnancy, her FT4 levels (0.52 - 1.27) were commensurate with her associated L-T4 dosages (25 - 150 mcg/day), consistent with a mid-FT4 level in accord with her calculated Ideal Body Weight dosage of 94 mcg/day. Likewise, her TSH levels (37 - 1.13) were inversely commensurate with her FT4 levels and L-T4 dosages. She delivered a normal baby, and since has been treated with L-T4, 150-175 mcg/d, and remained clinically euthyroid. Because of renal failure (GFR-36.3) with Type I Renal Tubular Acidosis, she was started on a urine alkalizing agent, sodium citrate/citric acid (SC/CA), 20 mg orally every 6 hrs. Since delivery, the patient’s FT4 levels have been very erratic and non-commensurate with her L-T4 dosages. In the past 14 mos. she has been on L-T4 dosages of 150-175 mcg/d (aver: 172 mcg/d). Her FT4 levels (ranging from 0.17 to 1.51 [aver: 0.89]), however, have continued to correlate very closely with her TSH levels (0.397 to 373 [aver: 68.7]). Notably, her four highest TSH levels were 373, 177, 134 and 122. She credibly insists on full compliance with her L-T4 therapy, never taking the medication within an hour of having breakfast or taking her other medications, which included ferrous sulfate and SC/CA. Interestingly, the highest TSH level recorded before starting SC/CA was only 24.9, associated with a low FT4 level of 0.66. Discussion: Evaluation focused on (1) the high levels of TSH, and (2) the postpartum lack of correlation of her FT4 levels and her L-T4 dosages. Regarding the former, extensive thyrotroph hyperplasia was not evident on pituitary MRI (though not ruling out lesser hyperplasia) and very high TSH levels are occasionally observed in patients hypothyroid for years. Resistance to Thyroid Hormone and TSH-producing pituitary adenoma were not likely in view of the close correlation of her TSH and FT4 levels, and her occasional near-normal TSH and FT4 levels. Human Anti-Mouse Antibodies (HAMA) and Macro-TSH were ruled out by assay. TSH Receptor Resistance to TSH could not be ruled out for lack of available assays and genetic analysis. Her normal absorption of L-T4 during pregnancy argues against chronic intrinsic malabsorption. Conclusion: Malabsorption of L-T4 relating to drug interference from ferrous sulfate and/or GI alkalinization from use of SC/CA, in a patient with thyrotroph hyperplasia from long-term Hashimoto’s hypothyroidism would appear to be the most likely, though complex, explanation.

Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center

Resistance to thyroid hormone (RTH), characterized by persistent hyperthyroxinemia with non-suppressed thyrotropin (TSH), is mostly caused by mutations in thyroid hormone receptor beta gene (THRB). Two differential diagnoses should be considered due to similar clinical and laboratory findings: TSH-producing pituitary adenoma (TPA) and Familial Dysalbuminemic Hyperthyroxinemia (FDH). The aim of this study is to describe our single tertiary center experience in the molecular diagnosis of RTH in Brazilian patients, analyzing their clinical and laboratory characteristics and the most common differential diagnosis. We enrolled 30 subjects with clinical and laboratory features of RTH. Patient´s evaluations included clinical examination, thyroid hormone profile and imaging tests. Sequencing analysis for THRB hot spot region was conducted on all patients, and those without mutations in beta isoform of the thyroid hormone receptor (TRβ) (non-TR-RTH) were investigated for albumin gene (ALB) mutation. Seventeen patients presented mutations in TRβ (RTHβ); six were non-TR-RTH, three had a diagnosis of FDH with a mutation in ALB, and four were diagnosed with TPA. Two characteristics were different to what is commonly described in the literature: higher serum TSH levels in RTHβ patients when compared to the non-TR-RTH group, but this difference did not extend to free T4 (FT4) level; also the percentage of non-TR-RTH was higher than what was reported in other series. In the present series, most cases were RTHβ with higher levels of TSH. We described three novel mutations in THRB (p.M313V, p.R320G and p.R438P) and the first patients with FDH molecular diagnosis (p.R242H) documented in Brazil.

Seven Familial Dysalbuminemic Hyperthyroxinemia Cases in Three Unrelated Japanese Families and High-Performance Liquid Chromatography Analysis of the Thyroxine Binding Profile

Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. One- and 2-step immunoassays of serum samples from FDH patients (e.g., Japanese patients) with the HSA R218P mutation can yield false-positive free thyroxine (FT4) results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of thyroid-stimulating hormone (TSH) (e.g., syndrome of resistance to thyroid hormone, TSH-producing pituitary adenoma), even when multiple assays are used. To investigate T4 to HSA binding, we examined serum samples from 7 patients from 3 Japanese families with FDH. Clinically, abnormal thyroid function tests were noted in pregnant Patient 1. Patients 2 and 3 had histories of inappropriate treatment with antithyroid drugs and surgery. All patients and affected family members were diagnosed with FDH using direct sequencing analysis. Gel filtration high-performance liquid chromatography was used for the biochemical analyses. 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. The results for the albumin effluent from healthy volunteer and TSHoma patient sera showed no corresponding TT4 peak. 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. F = free; FDH = familial dysalbuminemic hyperthyroxinemia; HPLC = high-performance liquid chromatography; HSA = human serum albumin; PCR = polymerase chain reaction; SITSH = syndrome of inappropriate secretion of TSH; T = total; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WT = wild-type.

Surgical Treatment and outcome of TSH-producing pituitary adenoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A Plurihormonal TSH-Secreting Pituitary Microadenoma: Report of a Case with an Atypical Clinical Presentation and Transient Response to Bromocriptine Therapy.

Inappropriate secretion of thyrotropin (TSH) is a rare cause of hyperthyroidism, and it is caused by either a TSH-producing pituitary adenoma (usually a macroadenoma) or to selective pituitary resistance to thyroid hormone. The case of a 31-yr-old male who presented with clinical features of thyrotoxicosis, including episodes of thyrotoxic paralysis, and a thyroid profile characterized by free hyperthyroxinemia and hypertriiodothyronemia with a nonsuppressed, inadequately normal TSH is reported. Dynamic testing showed both, lack of TSH stimulation by thyroid-releasing hormone (TRH), and lack of suppression by T3, consistent with autonomous TSH secretion. Pituitary MRI revealed a microadenoma. Seventy five percent of the patients serum TSH immunoreactivity eluted as u-subunit in Sephadex G-100 chromatography. A diagnosis of TSH-secreting microadenoma was established, and the patient was treated successfully with bromocriptine, which resulted in both clinical and biochemical resolution of his hyperthyroidism. Two months later, he became hyperthyroid again during bromocriptine therapy. Octreotide was started with adequate control of his symptoms and normalization of his free T4 level. He eventually underwent transsphenoidal surgery with successful resection of a chromophobic microadenoma which immunostained for TSH, growth hormone (GH), luteinizing hormone (LN), and follicle-stimulating hormone (FSH). One month postoperatively he is clinically and biochemically euthyroid on no medications.

Basic Fibroblast Growth Factor Expression by Two Prolactin and Thyrotropin-Producing Pituitary Adenomas.

We investigated the expression of basic fibroblast growth factor (bFGF) in an aggressive type of PRL and TSH-producing pituitary adenoma. Immunocytochemistry and electron microscopy were used to characterize the tumors removed from two patients. lmmunoassays were used to measure hormone and bFGF levels in vitro and in vivo. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect bFGF mRNA expression by these tumors. Morphologically, these tumors were characterized by an unusual plurihormonal pattern with expression of PRL and TSH and the ultrastructural characteristics of the silent subtype 3 adenoma; in addition, both adenomas displayed marked interstitial fibrosis. bFGF was measurable in the circulation of these patients ranging from 7.5-20.5 pg/mL (normal < 1 pg/mL). bFGF concentrations were reduced following surgical adenomectomy. bFCF in culture media was present in concentrations of 197-387 pg/24h/10(5) cells. bFGF mRNA expression was identified in both adenomas examined. bFGF levels were unaltered in the culture media and in the serum of patients following GnRH and TRH treatment. In conclusion, the expression of bFGF by these plurihormonal pituitary adenomas suggests the possibility that it may play a role in the development of fibrosis and tumor cell proliferation of this unusual type of pituitary neoplasm.

Establishment and characterization of a malignant epithelioid hemangioendothelioma from mouse thyroid tumor.

A mouse epithelioid hemangioendothelioma (mEHE) cell line, passagable in vivo without TSH stimulation, was established from a thyroid tumor. Before establishment of the cell line, the primary thyroid tumor which was co-transplanted with a TSH-producing pituitary adenoma showed signs of hyperplasia and then transformed during several in vivo transplantable passages. The cell line which was established from an in vitro culture, was deficient in thyroid-specific differentiation function and had characteristics of endothelial cell origin such as vascular cavity formation and factor VIII expression. The cell growth of mEHE/CH1-5 cell lines was independent of TSH but was inhibited by c-AMP and vitamin D3. c-Myc proto-oncogene expression was also suppressed by vitamin D3 treatment. Both serum depletion and heparin treatment induced morphological changes in mEHE/CH 5 from an epithelial cell-like to an endothelial cell-like shape. Immunohistochemical analysis showed that epithelial membrane antigen expression was decreased and factor VIII expression was increased in relation to the morphological changes. In a further in vivo transplantation experiment, the histology of the mEHE/CH5 cell tumor had an angiosarcoma-like structure. These results indicate that this cell line established from a thyroid tumor possesses both epithelial and endothelial characteristics. The mEHE/CH5 cells might provide a good model for analyzing thyroid tumorigenesis and allow functional characterization of endothelial cells.

Association of a thyrotropin-secreting pituitary adenoma and a thyroid follicular carcinoma

The different factors involved as etiological agents in thyroid cancer have in common long term thyroid follicle stimulation. On this base, a patient with a TSH-producing pituitary adenoma could be at high risk for developing thyroid cancer. A patient consulting for a single thyroid nodule was studied in our unit. He was diagnosed as having a TSH-producing pituitary adenoma and the Thyroid nodule was shown to be a follicular carcinoma following removed. We speculate that elevated TSH levels could have contributed to neoplastic transformation of the thyroid in this patient.

Clinical evaluation of highly sensitive thyroid stimulating hormone immunoradiometric assay (RIABEAD II) kit

To clarify clinical evaluation of highly sensitive thyroid stimulating hormone (TSH) immunoradiometric assay (IRMA) using RIABEAD II kit, we measured serum TSH and its changes after TRH test in normal subjects and patients with hyper- or hypothyroidism due to Grave's disease, TSH-producing pituitary adenoma and chronic thyroiditis or Refetoff's syndrome. In 12 normals, basal TSH (0.23-1.85 microIU/ml) increased in 2.29-18.85 microIU/ml 30 min after TRH test. In patients whose serum TSH and thyroid hormone showed less than 0.10 microIU/ml and more than normal level, respectively, no response of TSH to TRH was observed, while in patients whose serum TSH and thyroid hormone showed more than 3.5 microIU/ml and less than normal level, respectively, hyperresponse of TSH to TRH was observed. In patients with hyper- or hypothyroidism, changes in serum TSH after treatment were normalized a few months later after normalizing of thyroid hormone. In patients with TSH-producing pituitary tumor or Refetoff's syndrome, serum TSH increased. These results show that serum TSH using IRMA-(RIABEAD II) kit indicates a precise function of pituitary TSH.

Performance of direct equilibrium dialysis and analogue-type free thyroid hormone assays, and an immunoradiometric TSH method in patients with thyroid dysfunction

Direct equilibrium dialysis and analogue-type radio-immunoassays for free triiodothyronine (FT3) and free thyroxine (FT4) in serum were compared in 168 subjects with various states of thyroid function. A good diagnostic efficacy for FT3 and FT4 by either type of assay was observed in hyperthyroidism. In hypothyroidism the free thyroid hormone assays, particularly the FT3 assays, performed diagnostically less well, partly because patients with mild disease were included in the study. No significant differences in the percentages of misclassifications of thyroid dysfunction patients by corresponding dialysis and analogue assays were found. We observed a good linear correlation between dialysis and analogue methods for FT3 (r = 0.98) and FT4 (r = 0.97) in this study comprising out-patients not suffering from severe non-thyroidal disease, known from earlier studies in this and other laboratories to interfere in these assays. It is concluded that analogue assays may be used on out-patients in whom severe systemic diseases are less frequent than in hospitalized patients. There are, however, other limitations to the use of analogue assays than systemic diseases. We observed two euthyroid patients with thyroxine auto-antibodies causing very high FT4 concentrations as determined by analogue assay; their dialysable FT4 concentrations were normal. We also tested a recently developed immunoradiometric serum TSH assay, which was found to perform well in primary hypo- and hyperthyroidism. Serum TSH was elevated in one patient hyperthyroid because of a TSH-producing pituitary adenoma, and within the reference limits in a patient with secondary hypothyroidism.