The influence of body temperature on the human thyroid axis.

The work in this thesis stemmed from the observation that patients with primary hypothyroidism share many clinical manifestations with hypothermic individuals. It is recognised that hypothermia may complicate hypothyroidism and hypothermic myxoedema coma is a particularly serious complication with a high mortality. There is much controversy about the best way of managing the condition and disagreement about whether 'rewarming' or urgent administration of thyroid hormones is beneficial or harmful. The studies in this thesis attempt to determine the relationship of body temperature and the thyroid axis and then assess the contribution of a subnormal body temperature to the clinical syndrome of hypothyroidism. The sections of the thesis follow a logical sequence. After a review of the interrelationship between the nervous system and the thyroid with particular reference to the regulation of TSH secretion, current knowledge of the interrelationship between diurnal rhythms in body temperature and TSH is analysed. Earlier studies had established (mostly in animals) that exposure to cold and heat influences TSH secretion by a central nervous pathway. Finally, the techniques available for the study of peripheral thyroid hormone actions are critically evaluated (Chapter 5). Alteration in serum enzymes were assessed and selected methods established in the laboratory. The first need was to develop an improved sensitive radioimmunoassay for TSH (Chapter 2) which demanded an intensive period of laboratory development, unfortunately now overtaken by a series of double monoclonal antibody methods which outstrip the improvements achieved. The first study was on the effect of cold exposure on thyroid function in normal subjects (Chapter 3) in which the concomitant elevations of circulating noradrenaline, TSH, T4 and T3 raises the possibility that the catecholamine plays a key role in adaptation to cold by its activation of the hypothalamic pituitary thyroid axis at several levels. Secondly, it was shown that the circadian inverse relationship between TSH and body temperature could be abolished by warming (Chapter 4), suggesting that body temperature has a key role in regulating circulating TSH. In order to evaluate to what extent the peripheral action of thyroid hormones can be affected by alterations in tissue responsiveness (as distinct from a marked alteration of circulating hormone levels), a comparison was made in patients with thyrotoxicosis of the effects of propranolol and carbimazole (Chapter 6). Propranolol has been used in the treatment of thyrotoxicosis. The actions are, of course, known to be complex, involving generalised beta adrenergic blockade, an effect on membrane stabilisation and inhibition of conversion of thyroxine to triiodothyronine. It was of interest that during propranolol administration none of the parameters studied showed any tendency to change towards normality from the values associated with the hyperthyroid state whilst a 'fixed dose' regime of Carbimazole resulted in euthyroid and occasionally hypothyroid responses. It would appear that the benefits of propranolol in thyrotoxicosis are chiefly due to its actions on the sympathetic nervous system. When hypothyroid subjects were warmed (Chapter 7) cell membrane permeability to certain enzymes decreased and systolic time intervals increased. The latter effect occurred before T4 and T3 levels fell as a result of warming. Overall, these observations suggest that warming hypothyroid patients may have an adverse effect on ventricular function. In contrast, nerve conduction velocity and motor responsiveness improved after warming, although sensory thresholds remained abnormal. All abnormalities could be corrected with time when replacement therapy was adequate.