The Thyrotropin Receptor and the Regulation of Thyrocyte Function and Growth*

IN classical physiology, the main regulation of the thyroid gland involves a positive control by pituitary TSH. The pituitary thyrotrophs that synthesize and secrete TSH are submitted to tonic stimulation by the hypothalamic TRH and to negative feedback by T3, which is generated in these cells from plasma T4 (1, 2). The predominant role of TSH in thyroid regulation is exemplified by physiological experiments and pathological situations. Hypophysectomy, or treatment with thyroid hormones that reduces plasma TSH levels without interfering with other pituitary functions, almost abolishes thyroid function and greatly reduces the weight and cell mass of the gland. Conversely, chronic inhibition of the synthesis of thyroid hormones, and thus of their secretion, which greatly enhances TSH plasma levels, enhances thyroid growth and iodine metabolism upstream from the inhibited step. In pathology, hyperthyrotropinemia caused by pituitary adenomas induces hyperthyroidism and goiter. Hypopituitarism or an isolated TSH deficiency causes hypothyroidism and thyroid atrophy. Although the recent findings of receptors and effects of various cytokines, growth factors, and neurotransmitters in the thyroid may convey another impression, TSH and its receptor constitute the main regulatory pathway of the thyroid (3). of the thyroid (3). The predominant role that TSH plays in the activation of the cAMP cascade in thyroid regulation is exemplified by the hypothyroidism found in patients with Albright's hereditary osteodystrophy and by the hyperthyroidism of McCune-Albright syndrome patients who have, respectively, a congenital deficiency or a stimulatory mutation of as, the GTP binding protein that activates adenylate cyclase (4, 5). Of course, the activity of the TSH receptor and its dependent cascades is modulated by a whole network of regulatory agents and receptors. The main thyroid-specific control is exerted by iodide, presumably through an oxidized derivative. Various neurotransmitters (acetylcholine, norepinephrine, adenosine, etc.), local hormones (prostaglandins, atrionatriuretic factor, etc.), growth factors (epidermal growth factor, insulin-like growth factors, etc.) and cytokines interferon, tumor necrosis factor (TNF), and others, also regulate thyroid metabolism, but the agents involved and their effects vary from one species to another and the physiological role of these agents remains unknown (3, 6).