Defects In Hormone Synthesis Research Articles

Hipotireoidismo congênito: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, with an incidence of 1:2,000 to 1:4,000 live births and it is a leading preventable mental retardation. Neonatal Screening Programs allow early identification of the disease and the adequate treatment of affected children can avoid the complications related to deprivation of the hormone. Most cases of primary congenital hypothyroidism (85%) are due to thyroid dysgenesis (ectopia, hypoplasia or agenesis) while the remaining result from defects in hormone synthesis. Affected children (> 95%) usually have no symptoms suggesting the disease at birth. The most frequent symptoms and signs are prolonged neonatal jaundice, hoarse cry, lethargy, slow movements, constipation, macroglossia, umbilical hernia, large fontanelle, hypotonia and dry skin. Around the world, various strategies are used for the screening of the CH. In Brazil, screening for CH is mandatory by law and usually done by serum TSH in dried blood collected from the heel. The recommended age for performing this test is after 48 hours of life until the 4th day. Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum.

A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene

Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.

Goitrogenic and estrogenic activity of soy isoflavones.

Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate.

Genetic defects in thyroid hormone synthesis.

Thyroid hormone synthesis requires a normally developed thyroid gland, a properly functioning hypothalamic-pituitary-thyroid axis, and sufficient iodine intake. This article focuses on genetic defects in this axis. Defects that are primarily of developmental origin are discussed in our associated article in this issue. Defects in hormone synthesis usually are associated with the development of a goiter, provided that the bioactivity and action of thyrotropin (TSH) are not impaired. In contrast, hypoplasia of the gland may be caused by developmental defects, bioinactive TSH, or resistance to TSH at the level of the receptor or its signaling pathway. At the other end of the spectrum, hyperthyroidism may result from gain of function mutations in genes regulating growth and function.

Genetic regulation of thyroid development.

Normal thyroid function is essential for development, growth, and metabolic homeostasis. The prerequisites for an euthyroid metabolic state include a normally developed thyroid gland, a properly functioning system for thyroid hormone synthesis, and sufficient iodine intake. Defects in any of the essential steps in thyroid development or thyroid hormone synthesis may result in morphologic abnormalities and impaired hormonogenesis. These defects can be partial or complete, leading to varying degrees of hypothyroidism. Morphologic alterations associated with congenital hypothyroidism include the absence of detectable thyroid tissue, ectopic tissue, thyroid hypoplasia, or a goitrous thyroid. However, in some patients with hypothyroidism, the thyroid is of normal size. This article focuses on defects in thyroid development. Recent insights into the developmental regulation of the calcitonin-producing C cells will not be discussed, and defects in hormone synthesis are discussed in an accompanying article.

Hypothyroidism due to enzyme defects.

Summary Defects in thyroid hormone production, transport and utilization are classified. Particular attention is given to inherited intrathyroidal defects in hormone synthesis which impair thyroid function and lead to goitre formation and hypothyroidism. Anomalies in biosynthesis may also result from disease or drugs. Reference is made to the derangement of iodine metabolism that results from iodine deficiency and from insufficient TSH. Illustrative clinical problems with regard to transport and utilization are quoted, and it is inferred that they lie in rather neglected areas. Throughout an attempt has been made to show how the clinical problems that are encountered in practice may, by the techniques of investigation available to us, be related to the theoretical list of defects that are included in the classification.

Iodide trapping without organification in a transplantable rat thyroid tumor.

The present report describes a transplantable rat thyroid tumor that concentrates 40–70% of an injected dose of I131-iodidc and loses it rapidly with a half life, of 4–8 hours. The I131 in the tumor is 98–99% iodide as judged by tri-chloracetic acid solubility, chromatography and dialysis. The remainder of the I131 is organically bound and exists in the “participate” fraction. Iodide accumulation in vivo appeared to be independent of the level of thyrotropic hormone. Slices of the tumor concentrate iodide with a gradient (T/M ratio) ranging from 8 to 44.The gradient is largely abolished by various anions such as C104−, SeCN−, SCN− and by certain agents which uncouple oxidative phosphoryla-tion, such as dinitrophenol and dicumarol. Thyroxine and triiodothyronine have no significant effect on the T/M ratio at 10−4M. The defect in hormone synthesis seems to lie with the iodinating system since unlabcled thyroglobulin appears to be present. The ability to deiodinate L-diiodotyrosine has also been lost.

The nontoxic nodular hyperplastic goiter.

RECENT studies on sporadic goitrous cretinism1 2 3 4 5 have called attention to the interesting paradox of hypothyroidism associated with a hyperplastic nodular goiter. These studies have demonstrated an intrinsic defect within the thyroid gland in its synthesis of thyroid hormone that can occur at different stages, either in the binding of iodine to tyrosine or in the conversion of diiodotyrosine to thyroxin. Furthermore, judging by the different degrees of hypothyroidism in cretins, the defect in hormone synthesis may be either partial or complete. Spontaneous return of thyroid function to normal and the rarer occurrence of hyperthyroidism6 in some cretins suggest the possibility . . .