John T. Nicoloff

The role of glucocorticoids in the regulation of thyroid function in man

The diurnal variation in thyroidal iodine release previously observed in euthyroid subjects appears to correlate with variations in serum immunoassayable thyrotropin (TSH). The hypothesis is advanced that this diurnal rhythm seems to be primarily regulated by a negative feedback action of circulating hydrocortisone. The administration of maintenance doses of hydrocortisone to patients with primary adrenal insufficiency and pharmacological doses to euthyroid subjects was accompanied by an acute suppression in both thyroidal iodine release and serum TSH values. An escape from glucocorticoid suppression was observed to occur in 2 or 3 days with the resumption of a near-normal thyroidal iodine release rate but was accompanied by a dampening or absence of the normal diurnal rhythm. Withdrawal of pharmacological doses of glucocorticoids in euthyroid subjects and maintenance doses in primary hypoadrenal patients was accompanied by transient stimulation of both serum TSH and thyroidal iodine release values. The study of a patient before and after cryohypophysectomy indicated that the rebound response in thyroid release after steroid withdrawal may be a useful testing procedure to indirectly assess the hypothalamicpituitary reserve capacity of TSH.

A new method for the measurement of thyroidal iodine release in man

A new method is described for the detection of variations in the release rate of all iodinated products by the thyroid gland in man. (125)I was employed to endogenously label the thyroid gland, and a parenterally administered (131)I thyroxine dose was used to generate a (131)I reference source. Thyroidal iodine release activity was quantitatively assessed by the measurement of variations in (125)I/(131)I ratio values obtained in timed urine samples. Diurnal variation in thyroid release patterns was observed in euthyroid subjects which was promptly suppressed by exogenous triiodothyronine administration and was simulated by the intramuscular injection of 0.25-0.50 U of bovine thyrotropin. The zenith value occurred at 4:00 a.m. +/-3.4 hr (SD) and the nadir at 5:00 p.m. +/-3.6 hr. The absence of a diurnal pattern in patients with thyrotoxicosis and in secondary hypothyroidism indicated that this diurnal fluctuation was under thyrotropin (TSH) regulation. This new method also promises to be a useful tool for the study of the intrathyroidal recycling of iodide from the iodotyrosine pool and the detection of factors which may acutely alter thyroid function.

Estimation of thyroxine distribution in man

A group of 13 normal subjects were evaluated for their extrathyroidal thyroxine distribution. The method employed the measurement of the acute plasma disappearance of a thyroxine-(131)I tracer and its concomitant uptake into the liver and forearm. The analysis of these parameters allowed the theoretical construction of a four compartmental mathematical model system comprised of the plasma, extracellular fluid, hepatic, and extrahepatic thyroxine pools. The results of this analysis revealed that the exchange of thyroxine from the plasma into the hepatic and extrahepatic cellular fluid spaces appeared, in general, to be rapid, while the uptake into the extrahepatic tissues was relatively slow. The calculated distribution of thyroxine at equilibrium was estimated to be 14% in liver, 34% in extrahepatic tissues, and 26% each in the plasma and extracellular fluid pools in this group of normal subjects.

A new method for the measurement of acute alterations in thyroxine deiodination rate in man.

A newly devised dual labeled iodine isotopic method is described for the detection and quantitation of alterations in thyroxine (T(4)) deiodination rate in man. This method employs the principle of a constant (125)I infusion to serve as a reference source for the generation of (131)I derived from the deiodination of T(4)-(131)I. Measurement of these two iodide isotopes are made in serially timed urine collections and are expressed in terms of a ratio value. Using this technique, it was possible to measure accurately the effects of a single dose of 6-propylthiouracil (6-PTU) in producing inhibition of T(4) deiodination in euthyroid subjects. It was also possible to assess the time of onset, duration of action, and degree of inhibition produced by 6-PTU. Employing single doses of 6-PTU, ranging from 100 to 1000 mg, there was found to be a log dose relationship with a degree of inhibition observed in T(4) deiodination. In control studies T(4) deiodination rate was found to be constant for periods ranging up to 72 hr in normal ambulating subjects. The acute administration of many other agents was employed in an attempt to alter the T(4) deiodination rate. These included diphenylhydantoin, methimazole, triiodothyronine, thyroxine, thyroid stimulating hormone (TSH), adrenocorticotropin (ACTH), hydrocortisone, predinsolone, potassium iodide, epinephrine, and oxytocin. No detectable change in T(4) deiodination rate was observed with these agents in the dosage ranges employed in this study. The lack of any observable alteration in the T(4) deiodination rate in response to this array of drugs and hormones appears to indicate that the availability of T(4) to intracellular sites of deiodination and possibly action is well modulated to resist abrupt changes.