A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma.

Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary, despite elevated levels of thyroid hormone thyroxine (T4) and triiodothyronine (T3). Thyrotropin-secreting tumors are presumed to represent clonal expansion of abnormal cells. Because the diagnosis of TSH-secreting tumors tends to be delayed and curative surgical resection remains under 50%, early diagnosis is paramount. Current diagnostic strategies suggest that RTH patients are distinguishable from patients with TSH-secreting pituitary tumors by the use of standard laboratory tests and imaging. Here, we present a woman in whom the standard evaluation for inappropriate TSH secretion was insufficient to distinguish these entities. The patient had a low-normal TRH stimulation test and an unmeasurable alpha-glycoprotein subunit level; however, a pituitary magnetic resonance imaging (MRI) revealed an adenoma. More testing using a T3 suppression test supported a RTH diagnosis and a R438H mutation was found in the TR-beta gene. To our knowledge, this represents the first report of an apparently incidental pituitary adenoma in the setting of documented resistance to thyroid hormone. As such, it raises the question of whether RTH predisposes to pituitary hyperplasia and adenoma development.     

Hyperthyroidism due to inappropriate secretion of thyrotropin in 10 patients.

PURPOSE: The syndrome of inappropriate thyroid-stimulating hormone (TSH) secretion, characterized by elevated serum free thyroxine and triiodothyronine levels in association with measurable serum TSH concentrations, remains an uncommon cause of hyperthyroidism that is being recognized with increasing frequency. The hyperthyroidism may be due to either neoplastic pituitary TSH secretion or selective pituitary resistance to thyroid hormone. In an effort to better understand this rare cause of hyperthyroidism, we undertook a retrospective analysis of our institution's experience with this condition. PATIENTS: We reviewed our cumulative experience (10 patients) with hyperthyroidism due to the syndrome of inappropriate secretion of TSH. RESULTS: Six patients were diagnosed with TSH-secreting pituitary adenomas and four were found to have selective pituitary resistance to thyroid hormone. One patient with tumor had a TSH-secreting pituitary adenoma in the setting of multiple endocrine neoplasia syndrome. In all patients with tumor, hyperthyroidism was successfully treated with transsphenoidal adenomectomy with or without pituitary radiotherapy. All four patients with pituitary resistance had thyroid ablation or resection prior to their correct diagnosis. Therefore, therapy for this group of patients involved thyroid hormone replacement and efforts to suppress TSH hypersecretion. All 10 patients have done well clinically, with follow-up ranging from 2 weeks to 13 years. CONCLUSIONS: Adequate treatment exists for the two primary causes of TSH hypersecretion. TSH-secreting pituitary adenomas are treated with surgery and, if necessary, adjuvant pituitary radiotherapy. The results are generally good if the tumor is diagnosed and treated at an early stage. Primary therapy for hyperthyroidism due to selective pituitary resistance to thyroid hormone is aimed at suppression of pituitary TSH hypersecretion. The evaluation of any patient with hyperthyroidism must be thorough and, in some cases, should include measurement of TSH to determine the presence of inappropriate secretion. Eliminating this diagnosis will help avoid improper and potentially harmful treatment of hyperthyroid patients.     

Thyroid-pituitary function in eight anencephalic infants

The function of the thyroid pituitary axis was investigated in 8 anencephalic infants with no hypothalamus. Thyrotrophin (TSH), thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyrone (reverse T3 and rT3) were measured in the cord blood in 5 cases and during the first 4 h of life in 3 cases. TSH response to synthetic thyrotrophin-releasing hormone (TRH) (200 microgram iv) was carried out in two cases and thyroid hormone response to bovine TSH (5 IU iv) was evaluated in 3 cases. The following results wre obtained: 1) The pituitary gland was found in all infants and the thyroid was normal both grossly and by microscopic sections. 2) TSH levels at birth were normal but there was no spontaneous post-delivery surge. 3) T4 and T3 values at delivery were within normal range, but no T3 increase was present after birth. rT3 levels at birth were higher than normal in 3 cases. 4) Administration of TRH caused a marked and rapid TSH release. 5) Thyroid hormone response to TSH was normal. The present findings suggest that in the anencephalic foetus both pituitary TSH-secreting cells and the thyroid gland do develop despite the absence of the hypothalamus and are able to function if adequately stimulated.     

Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone

Mutations in the thyroid hormone receptor-beta gene (TR beta) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TR beta PV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TR beta(PV/+) mice but not in TR beta(PV/PV) mice. In TR beta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TR beta(PV/+) or TR beta(PV/PV) mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T(3) target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner.     

Thyrotropin-secreting pituitary adenoma presenting as hypokalemic periodic paralysis

Thyrotropin (TSH)-secreting pituitary adenoma presenting with hypokalemic periodic paralysis is extraordinarily rare and may be misdiagnosed. We describe a 44-year-old man who suffered from acute muscle weakness and inability to ambulate upon awakening in the morning. Physical examination showed hypertension, tachycardia, and symmetrical flaccid paralysis of all extremities. The major biochemical abnormality was hypokalemia (K+, 2.0 mmol/L) with low urine K+ excretion. A thyroid function study revealed elevated thyroid hormone levels and inappropriately high TSH concentrations (2.10 microU/mL). Brain magnetic resonance imaging delineated a pituitary tumor with suprasellar extension. After trans-sphenoidal removal of tumor, he became clinically and biochemically euthyroid without any further attack of paralysis. Pathological findings confirmed a TSH-secreting adenoma with exclusive TSH immunostaining. TSH-secreting pituitary adenoma must be kept in the differential diagnosis in any thyrotoxic periodic paralysis patients with detectable TSH levels to avoid delaying diagnosis and management.     

AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH beta and alpha subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH beta and alpha mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.     

Thyrotropin-secreting pituitary adenomas: biological and molecular features, diagnosis and therapy

Central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma is a rare cause of hyperthyroidism, representing 0.5-1.0% of all pituitary adenomas. The etiopathogenesis of TSH-secreting-adenomas is unknown and no definite role for various oncogenes has been proven. Patients with TSH-secreting adenoma usually present with signs and symptoms of hyperthyroidism milder than those in patients with hyperthyroidism of thyroid origin, in addition to symptoms secondary to mass effects of the pituitary tumour. Mixed pituitary tumours co-secrete growth hormone and prolactin. The characteristic biochemical abnormalities are normal or high serum TSH concentrations in the presence of elevated total and/or free thyroid hormones concentrations. Measurement of markers of peripheral thyroid hormone action and dynamic tests may aid in the differential diagnosis with the syndrome of resistance to thyroid hormone. Neuroimaging is fundamental to visualize the pituitary tumor. Therapy of TSH-secreting adenomas can be accomplished by surgery, radiation therapies, and medical treatment with somatostatin analogs or dopamine agonists. Nowadays, and in contrast with the first reports on this rare disease, most patients are well controlled by current therapies.     

Coexistence of TSH-secreting pituitary adenoma and autoimmune hypothyroidism

OBJECTIVE: TSH-secreting pituitary adenomas account for about 1-2% of all pituitary adenomas. Their diagnosis may be very difficult when coexistence of other diseases masquerades the clinical and biochemical manifestations of TSH-hypersecretion. CLINICAL PRESENTATION: A 41-yr-old female patient, weighing 56 kg, was referred for evaluation of an intra- and suprasellar mass causing menstrual irregularities. Eight yr before, the patient had been given a diagnosis of subclinical autoimmune hypothyroidism because of slightly elevated TSH levels and low-normal free T4 (FT4). Menses were normal. Despite increasing doses of levo-T4 (L-T4; up to 125 microg/day), TSH levels remained elevated and the patient developed mild symptoms of hyperthyroidism. After 7 yr, the menstrual cycle ceased. Gonadotropins were normal, whereas PRL level was elevated at 70 microg/l and magnetic resonance imaging (MRI) of the hypothalamic- pituitary region revealed a pituitary lesion with slight suprasellar extension. The tumor was surgically removed and histological examinations revealed a pituitary adenoma strongly positive for TSH. Three months after surgery the patient was well while receiving L-T4 75 microg/day and normal menses had resumed. MRI of the hypothalamic-pituitary region showed no evidence of residual tumor. At the last follow-up, 16 months after surgery, serum TSH, free T3 (FT3), and FT4 levels were normal. CONCLUSIONS: Coexistence of autoimmune hypothyroidism and TSH-secreting pituitary adenoma may cause further delays in the diagnosis of the latter. In patients with autoimmune hypothyroidism, one should be aware of the possible presence of a TSH-secreting pituitary adenoma when TSH levels do not adequately suppress in the face of high doses of L-T4 replacement therapy and elevated serum thyroid hormone levels.     

Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice

During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h.Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.     

Cyclic changes in the expression of steroid receptor coactivators and corepressors in the normal human endometrium

To examine the sex steroid-dependent growth mechanisms of the human endometrium, the expression of steroid receptor coactivators [steroid receptor coactivator-1 (SRC-1) and p300/CREB-binding protein (p300/CBP)] and corepressors (nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors) was examined by immunohistochemistry, using 50 samples of normal endometria, and was compared with that of estrogen receptors (ER), progesterone receptors (PR), and proliferation marker Ki-67. In addition, actual binding of the coactivators to ER or PR was analyzed by immunoprecipitation. The expression of SRC-1 was diffusely observed in glandular and stromal cells in the proliferative phase and drastically decreased in the secretory phase. Such change in the expression pattern of SRC-1 resembled that of ER, PR, and Ki-67. On the other hand, p300/CBP expression was relatively constant throughout the menstrual cycle, with slight predominance in the proliferative phase. The expression of corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors was focal in the endometrium. Immunoprecipitation, using tissue samples of both proliferative and secretory phases, revealed the complex formation between the coactivators and receptors. Binding of SRC-1 to ER was observed in the proliferative (but not in the secretory) endometrium. In contrast, binding p300/CBP to ER was noted in the endometria of both phases. Complex formation between p300/CBP and PR was noted in the secretory endometrium, whereas that between SRC-1 and PR was not apparent. Accordingly, we showed the expression pattern of steroid receptor coactivators and corepressors in the normal endometrium. Cyclic change in the expression of SRC-1 during the menstrual cycle might be important in the estrogen-action for the glandular and stromal cells.     

The effect of growth hormone on the plasma levels of T4, free-T4, T3, reverse T3 an TBG in hypopituitary patients

The plasma concentrations of thyroxine (T4), free thyroxine (free-T4), triiodothyronine (T3), reverse triiodothyronine (rT3), TSH and thyroxine-binding globulin (TBG) were measured in 19 children suffering from idiopathic growth hormone deficiency. Blood was taken before and one month after growth hormone treatment. Ten patients were hypothyroid (group 1) and 9 were euthyroid (group 2). The basal T3 and rT3 levels correlated well with the T4 concentrations. Free-T4 levels were very low in all the hypothyroid patients and proved to be the most reliable index of TSH deficiency. TBG concentration was high in th hypopituitary patients regardless of their thyroid function. Following growth hormone treatment T4, free-T4 and rT3 levels fell in both groups. The T3 concentration rose in group 1 but no change was seen in group 2. There was a significant correlation between the changes of T4 and T3, such that the increase in T3 level was greatest in those with only a slight reduction of T4 concentration and no T3 increase was seen with more marked T4 decreases. The plasma TBG concentration is enhanced in growth hormone deficiency causing relatively high T4 values. Growth hormone treatment reduces T4 secretion and affects the peripheral metabolism of thyroid hormones resulting in an increase of T3 and a reduction of rT3 concentration.