Thyroid follicular cell carcinogenesis.

Ample information in experimental animals indicates a relationship between inhibition of thyroid-pituitary homeostasis and the developmental thyroid follicular cell neoplasms. This is generally the case when there are long-term reductions in circulating thyroid hormones which have triggered increases in circulating thyroid stimulating hormone. Such hormonal derangements leading to neoplasms have been produced by different regimens, including dietary iodide deficiency, subtotal thyroidectomy, and administration of natural and xenobiotic chemical substances. The carcinogenic process proceeds through a number of stages, including follicular cell hypertrophy, hyperplasia, and benign and sometimes malignant neoplasms. Given the interrelationship between the thyroid and pituitary glands, conditions that result in stimulation of the thyroid can also result in stimulation of the pituitary, with the development of hyperplastic and neoplastic changes. The progression of events leading to thyroid (and pituitary) neoplasms can be reversed under certain circumstances be reestablishing thyroid-pituitary homeostasis. Most chemicals that have induced follicular cell tumors seem to operate through inhibition of the synthesis of thyroid hormone or an increase in their degradation and removal. For some of these compounds, it appears that genotoxic reactions may not be playing a dominant role in the carcinogenic process. A seemingly small group of thyroid carcinogens seems to lack influence on thyroid-pituitary status and may in part be operating via their genotoxic potential. In contrast with the well-established relationship between thyroid-pituitary derangement and follicular cell neoplasms in animals, the state of information in humans is much less certain. At this time, ionizing radiation is the only acknowledged human thyroid carcinogen, a finding well established in experimental systems as well. Although humans respond to goitrogenic stimuli as do animals, with the development of cellular hypertrophy, hyperplasia, and under certain circumstances nodular lesions, disagreement exists as to whether malignant transformation occurs in any predictable manner. It would seem that if humans develop thyroid tumors following long-term derangement in thyroid-pituitary status, they may be less sensitive than the commonly used animal models.

Goitrogens and thyroid follicular cell neoplasia: evidence for a threshold process.

Thyroid neoplasia can result from many different causes. These include low iodine diets, subtotal thyroidectomy, radioactive iodine, natural goitrogens such as rape seed and cabbage, chemotherapeutic agents such as sulfathiazole, and pesticides such as amitrole. All of these appear to act through either direct or indirect interference with thyroid hormone synthesis. Decreased circulating levels of thyroid hormones in the blood result in increased release of thyroid-stimulating hormone by the anterior pituitary gland. This, in turn, results in hypertrophy and hyperplasia of the thyroid without a corresponding increase in blood thyroid hormone levels. Hyperplasia of the pituitary is also observed due to increased functional demand for continued production of thyroid-stimulating hormone. After prolonged stimulation of the pituitary/thyroid axis, hyperplasia may progress to neoplasia. Cessation of exposure prior to the induction of neoplasia results in a return to the normal state. It is clear that some degree of thyroid inhibition can be accommodated within the bounds of the normal feedback mechanism without the induction of either hyperplasia or neoplasia. A threshold for thyroid follicular neoplasia is therefore indicated.