PANEL DISCUSSION ON HYPERTHYROIDISM DR. LOUIS SOKOLOFF, Division of Mental Diseases, National Institutes of Health, Bethesda: Probably the earliest discovery concerning the action of the - thyroid hormone was its effects on heat production and O, consumption (2). The timing of this discovery reflects the fact that interest in the role of the thyroid developed at a time when calorimetry, direct and indirect, was in vogue. Stimulation of metabolic rate was a very profound effect, and this early observation has dominated our thinking concerning the action of the thyroid hormones ever since. It has led to an almost continuous search for a specific effect on energy metabolism to explain the mechanism of action of the thyroid hormone. About 15 years ago, it was found that thyroxine appeared to uncouple oxida- tive phosphorylation. The classic un- coupling agent, dinitrophenol (DNP), had JO'3 100 known to stimulate O, consumption, it was suspected that it, too, like DNP, might be an uncoupling agent. It was mainly through the work of Martins (3) and Hoch and Lipmann (4) that it was found that thyroxine does indeed depress oxidative phosphorylation. This discovery agreed with the historical bias that the thyroid hormone is primarily concerned with energy metabolism, and uncoupling of oxidative phosphorylation became widely accepted as the mechanism of action of .. ted thyroxine. a4 In actual fact, thyroxine does not act we like DNP. Although it does depress . ee ae phosphorylation and lowers the efficiency of oxidative phosphorylation, t.e., lowers th P/O ratio, it generally does not stimulatq@y; 4 Ae aaa oe Cia OE i at ah = . oe wf ny : ht cm O, consumption at the same time, at least not in vitro. Furthermore, if it were acting merely as an uncoupling agent, one might expect that other uncouplers might be effective in ameliorating thyroid deficiency states. They do not. Even DNP,which does stimulate the metabolic rate, has no other beneficial effect in hypothyroidism. Also, if one considers carefully the physiological consequences of the action of the thyroid hormone, then it becomes clear that all of its multiple effects cannot possibly be explained by an effect which results in a wasting of energy, which uncoupling of oxidative phosphorylation implies. Only its effects on O, consumption and heat production can be so explained. The thyroid hormone, however, has many other actions, for example, its effects on growth, maturation and development, and many of these suggest increased energy utilization rather than energy dissipation. It was considerations such as these that led us to doubt that uncoupling of oxidative phosphorylation could be the specifi mechanism of action of the thyroid hor mone. ~~ - sibly perchlorate therapy, or whether she should be treated with '™J. With this introduction, I think we can try to see what information is available which would guide us to the best conclusion. As stated, the first areas to be discussed will be the action of the thyroid hormones and the etiology of the disorder resulting in excess production of these hormones. I shall ask Dr. Sokoloff to review the former subject. been known to dissociate phosphorylation from electron transport and to result in | increased oxygen consumption and decreased ATP formation. Since thyroxine was also a substituted phenol and was 21 AEihseaSagal rash and hives over her entire body. It was finally concluded that this might be a reaction to sodium iodide and this agent was discontinued. Twenty-four hours later, her hives began to disappear, the articular signs began to clear up, and in a short time she was well again. Wewerefaced, then, with hyperthyroidism in a 16}-year-old girl who was allergic to the major agents used to prepare patients for surgery, for chronic medical treatment, or needed to restore euthyroidism. There followed considerable dispute as to whether operation should be performed anyway, with heavy sedation including reserpine, hypothermia, and pos- ' *. 1acne! 1764