Thyroid-stimulating Hormone Hypersecretion Research Articles

Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis.

This review covers new mechanistic information spanning the past 10 years relevant to normal and abnormal thyroid growth and function that may assist in the risk assessment of chemicals inducing thyroid follicular cell neoplasia. Recent studies have shown that thyroid regulation occurs via a complex interactive network mediated through several different messenger systems. Increased thyroid-stimulating hormone (TSH) levels activate the signal transduction pathways to stimulate growth and differentiation of the follicular cell. The important role of TSH in growth as well as in function helps to explain how disruptions in the thyroid-pituitary axis may influence thyroid neoplasia in rodents. New investigations that couple mechanistic studies with information from animal cancer bioassays (e. g., sulfamethazine studies) confirm the linkage between prolonged disruption of the thyroid-pituitary axis and thyroid neoplasia. New initiation/promotion studies in rodents also support the concept that chronic stimulation of the thyroid induced by goitrogens can result in thyroid tumors. Some of these studies confirm previous suggestions regarding the importance of chemically induced thyroid peroxidase inhibition and the inhibition of 3,3',5, 5'-tetraiodothyronine (T4, thyroxine) deiodinases on disruption of the thyroid-pituitary axis leading to thyroid neoplasia. Some comparative physiologic and mechanistic data highlight certain differences between rodents and humans that could be expected to confer an increased vulnerability of rodents to chronic hypersecretion of TSH. New data from epidemiologic and molecular genetic studies in humans contribute further to an understanding of thyroid neoplasia. Acute exposure to ionizing radiation, especially in childhood, remains the only verified cause of thyroid carcinogenesis in humans. Iodine deficiency studies as a whole remain inconclusive, even though several new studies in humans examine the role of dietary iodine deficiency in thyroid cancer. Specific alterations in gene expression have been identified in human thyroid neoplasia, linked to tumor phenotype, and thus oncogene activation and tumor-suppressor gene inactivation may also be factors in the development and progression of thyroid cancer in humans. An analysis by the U.S. EPA Risk Assessment Forum, prepared as a draft report in 1988 and completed in 1997, focused on the use of a threshold for risk assessment of thyroid follicular tumors. New studies, involving several chemicals, provide further support that there will be no antithyroid activity until critical intracellular concentrations are reached. Thus, for chemically induced thyroid neoplasia linked to disruptions in the thyroid-pituitary axis, a practical threshold for thyroid cancer would be expected. More information on thyroid autoregulation, the role of oncogene mutations and growth factors, and studies directly linking persistently high TSH levels with the sequential cellular development of thyroid follicular cell neoplasia would provide further confirmation.

Mechanistic data and risk assessment of selected toxic end points of the thyroid gland.

Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis, secretion, and metabolism of thyroid hormones. This includes (a) inhibition of the iodine trapping mechanism, (b) blockage of organic binding of iodine and coupling of iodothyronines to form thyroxine (T4) and triiodothyronine (T3), and (c) inhibition of thyroid hormone secretion by an effect on proteolysis of active hormone from the colloid. Another large group of goitrogenic chemicals disrupts thyroid hormone economy by increasing the peripheral metabolism of thyroid hormones through an induction of hepatic microsomal enzymes. This group includes central nervous system-acting drugs, calcium channel blockers, steroids, retinoids, chlorinated hydrocarbons, polyhalogenated biphenyls, and enzyme inducers. Thyroid hormone economy also can be disrupted by xenobiotics that inhibit the 5'-monodeiodinase that converts T4 in peripheral sites to biologically active T3. Inhibition of this enzyme by FD&C Red No. 3 lowers circulating T3 levels, which results in a compensatory increased secretion of thyroid-stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia, and an increased incidence of follicular cell tumors in 2-yr or lifetime studies in rats. Physiologic perturbations alone, such as the feeding of an iodine-deficient diet, partial thyroidectomy, natural goitrogens in certain foods, and transplantation of TSH-secreting pituitary tumors in rodents also can disrupt thyroid hormone economy and, if sustained, increase the development of thyroid tumors in rats. A consistent finding with all of these goitrogens, be they either physiologic perturbations or xenobiotics, is the chronic hypersecretion of TSH, which places the rodent thyroid gland at greater risk to develop tumors through a secondary (indirect) mechanism of thyroid oncogenesis associated with hormonal imbalances.

Syndrome of Resistance to Thyroid Hormone: Insights into Thyroid Hormone Action

Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene. Biochemically, the syndrome is defined by elevated circulating levels of free thyroid hormones due to reduced target tissue responsiveness and normal, or elevated, levels of thyroid-stimulating hormone (TSH). This "inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, where the pituitary secretion of TSH is suppressed. Patients with RTH usually present with goiter and an euthyroid or mildly hypothyroid metabolic state. Thus, pituitary resistance results in hypersecretion of TSH, which compensates, at least in part, for hormone resistance in peripheral tissues. Despite this compensation, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism. With the exception of a single sibship, which harbored a deletion of the entire coding sequence of the TR beta gene and a recessive pattern of inheritance, all other cases of RTH have been inherited in an autosomal dominant manner or have been de novo heterozygous mutations of the TR beta gene. The dominant pattern of inheritance is explained by the functional properties of the mutant receptors which act in a dominant negative manner to block the activity of normal TR alpha and TR beta receptors. Now that a large number of different RTH mutations have been identified, it is striking that the mutations are clustered within restricted domains in the carboxyterminal region of the receptor. Mutations in these regions have been shown to preserve critical receptor functions such as dimerization and DNA binding, while inactivating other activites such as T3 binding and transcriptional activation. The examination of patients with RTH and their mutated receptors has provided important insights into the mechanisms of thyroid hormone action, the structure-function relationship of the receptors, and the molecular mechanisms of dominant negative activity.

Dopamine suppresses thyroid‐stimulating hormone secretion in neonatal hypothyroidism

The infusion of dopamine, a hypophysiotropic catecholamine, which inhibits release of thyroid stimulating hormone (TSH), is the inotropic therapy of first choice in neonatal intensive care. Newborns with primary hypothyroidism are at increased risk of cardiocirculatory morbidity and are screened by measuring serum TSH concentrations. In an infant with both congenital heart disease and neonatal hypothyroidism, withdrawal of dopamine infusion was documented to evoke a doubling of serum TSH levels within 40 min, a finding suggestive of an inhibitory effect of dopamine administration on neonatal TSH hypersecretion. As a result, dopamine therapy may be a pitfall in TSH screening for neonatal hypothyroidism.

Pathophysiology of chemical injury of the thyroid gland

Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis and secretion of thyroid hormones. This includes: (1) inhibition of the iodine trapping mechanism (thiocyanate or perchlorate); (2) blockage of organic binding of iodine and coupling of iodothyronines to form thyroxine (T 4) and triiodothyronine (T 3) (e.g. sulfonamides, thiourea, methimazole, and aminotriazole, amongst others); (3) inhibition of thyroid hormone secretion by an effect on proteolysis of active hormone from the colloid (lithium or an excess of iodide). Another large group of goitrogenic chemicals disrupts thyroid hormone economy by increasing the peripheral metabolism of thyroid hormones through an induction of hepatic microsomal enzymes. This group includes CNS-acting drugs (phenobarbital, benzodiazepines), calcium channel blockers (nicardipine, nifedipine), steroids (spironolactone), retinoids, chlorinated hydrocarbons (chlordane, DDT, TCDD), polyhalogenated biphenyls (PCB, PBB), and enzyme inducers. Thyroid hormone economy also can be disrupted by xenobiotics that inhibit the 5′-monodeiodinase which converts T 4 in peripheral sites (e.g. liver and kidney) to biologically active T 3. Inhibition of this enzyme by FD&C Red No. 3, amiodarone, and iopanoic acid lowers circulating T 3 levels which results in a compensatory increased secretion of thyroid stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia, and an increased incidence of follicular cell tumors in 2-year or lifetime studies in rats. Physiologic perturbations alone, such as the feeding of an iodine-deficient diet, partial thyroidectomy, natural goitrogens in certain foods, and transplantation of TSH-secreting pituitary tumors in rodents also can disrupt thyroid hormone economy and, if sustained, increase the development of thyroid tumors in rats. A consistent finding with all of these goitrogens, be they either physiologic perturbations or xenobiotics, is the chronic hypersecretion of TSH which places the rodent thyroid gland at greater risk to develop tumors through a secondary mechanism of thyroid oncogenesis.

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.

The effects of xenobiotics on the structure and function of thyroid follicular and C-cells.

The mammalian thyroid gland is composed of 2 distinct endocrine cell populations concerned with the synthesis of 2 different classes of hormones. Follicular cells secrete the metabolically active iodothyronines whereas the C-(parafollicular) cells are concerned with the production of calcitonin, a hormone that influences blood levels of calcium and phosphorus, and bone cell metabolism. The synthesis of metabolic thyroid hormones is different than in other endocrine glands because the final assembly of hormone occurs within the follicular lumen. This extracellular synthesis of thyroid hormones is made possible by thyroglobulin, a glycoprotein synthesized by follicular cells. The secretion of thyroid hormones under the influence of pituitary thyrotrophin (TSH) from stores in the luminal colloid is initiated by elongation of microvilli and formation of pseudopods. FD&C Red No. 3 is a tetraiodinated derivative of fluorescein which in lifetime studies increases the incidence of thyroid follicular cell adenomas in male Sprague-Dawley rats. The striking changes in circulating levels of thyroid hormones and morphologic evidence of follicular cell stimulation are the result of alterations in the peripheral metabolism of thyroxine. An inhibition by FD&C Red No. 3 of 5'-deiodinase in the liver and kidney would explain the lower serum triiodothyronine (T3) levels. The pituitary, sensing the lowered circulating levels of T3, increased the secretion of thyroid stimulating hormone which resulted in the morphologic evidence of follicular cell stimulation in the long-term studies. Other xenobiotics increase the incidence of thyroid tumors in rodents by a direct effect on the thyroid gland to disrupt 1 of 3 or more possible steps in the biosynthesis of thyroid hormones. Physiologic perturbations alone, such as iodine deficiency or partial thyroidectomy, can disrupt thyroid hormone economy in rodents and, if sustained, increase the development of thyroid tumors. The wide variety of drugs, chemicals, and physiologic perturbations which increase thyroid tumor development appear to act through a secondary (indirect) mechanism to promote tumor development by causing a long-standing hypersecretion of thyroid stimulating hormone. Nodular and/or diffuse hyperplasia of C-cells occurs with advancing age in many strains of laboratory rats and in response to long-term hypercalcemia in certain animal species and human beings. Focal or diffuse hyperplasia often precedes the development of C-cell neoplasms. Radiation and the feeding of diets high in vitamin D resulting in hypercalcemia have been reported to increase the incidence of C-cell tumors in rats.

Clinical evaluation of SMS 201-995

Abstract. Long-acting somatostatin analogues such as SMS 201-995 (Sandoz) are being evaluated in a wide range of clinical indications, including gut neuroendocrine tumours and acrogemaly. Long-term continuous SMS 201-995 treatment has achieved useful symptomatic improvement in diarrhoea in 4 patients with metastatic VIPomas who had relapsed following previous treatment. Clinical improvement has outlasted suppression of VIP secretion (suggesting an additional direct antisecretory action of SMS 201-995) and has occurred despite expansion of hepatic metastases. In 6 patients with tumours secreting gastrin and/or glucagon, secretion of these peptides was acutely inhibited by SMS 201-995. However, endocrine and clinical responses to chronic treatment have been less consistent. SMS 201-995 is active orally at doses of 4–8 mg and when given thrice-daily to 6 patients with active acromegaly, suppressed mean 24-h growth hormone levels by 51–88%. Despite significantly reduced plasma insulin concentrations, glucose tolerance did not deteriorate. SMS 201-995 was also effective in suppressing thyroid-stimulating hormone (TSH) and thyroid hormone secretion in a patient with mild thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion. In all cases SMS 201-995 treatment has been been well tolerated and has few side-effects.

Effects of food restriction on cortisol, TSH and iodothyronine concentrations in the plasma of the newborn lamb.

The influence of food restriction, applied from birth to 36 h post partum, on neonatal thyroid function was studied in newborn Limousin x Romanov lambs. The control animals (n = 18) had free access to the mother and suckled ad libitum. Restricted lambs (n = 16) were removed from the mother and received limited amounts of colostrum in proportion to birth weight; 8 lambs were supplemented with lactose (30 g/l of colostrum). Plasma glucose and free fatty acid levels were significantly lower in restricted lambs, whereas urea levels were elevated. Plasma cortisol concentrations in control animals decreased during the period studied, but rose during the first 8 h of life in restricted lambs. Lactose supplementation only partially restored glucose and urea levels. Food restriction induced considerable modifications in neonatal thyroid function. The postpartum rise in plasma thyroid-stimulating hormone (TSH), thyroxine (T4) and free T4 levels occurring in control lambs was inhibited in restricted animals. However, the surge in plasma triiodothyronine (T3) levels was not affected, suggesting that this change was not related to physiological neonatal TSH hypersecretion. Thereafter, thyroid hormone concentrations decreased sharply during food restriction, whereas reverse T3 levels remained higher than in the controls. In response to these T4 and T3 deficiencies, plasma TSH levels rose only in lactose-supplemented animals. In agreement with the significant modifications in the values of the T3/free T4 and reverse T3/free T4 ratios, the abrupt changes in T3 and reverse T3 levels suggest that food restriction affected the peripheral conversion of T4 into T3 and reverse T3.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effect of radiation on thyroid function and tumor formation

Cellular injury coupled with hypersecretion of thyroid stimulating hormone (TSH) is considered the mechanism for radiation-induced thyroid tumors. This hypothesis was tested by administering 40 μCi of 131I to male and female rats. Serum thyroxine (T 4) decreased significantly overtime in male and female control and radiated animals. T 4 was essentially the same in 6- and 12-month-old radiated and control animals, but a significant decrease in T 4 was noted in radiated females at 21 months. TSH decreased overtime in control animals, but a significant increase in TSH was required in radiated animals to maintain T 4 levels. Thyrocalcitonin (TC) was significantly greater in 21-month-old control females than in males or radiated females. A significant increase in follicular cell thyroid neoplasms in radiated animals was associated with the elevated TSH levels. The importance of sex in thyroid tumor formation is illustrated by the fact that males had a significantly higher frequency of thyroid neoplasms than did females. C-cell hyperplasia and medullary thyroid carcinoma only occurred in control animals and accounted for their higher TC levels. This study confirms that administration of low doses of 131I leads to an increased frequency of thyroid tumor formation in rats and that direct cellular injury plus hypersecretion of TSH seem responsible for these radiation-induced tumors.