In a prospective study, we assessed the role of thyrotropin in the development of the low-thyroxine state that is associated with severe illness. We measured the serum thyrotropin and thyroid hormone concentrations longitudinally in 35 patients with hematopoietic cancer or aplastic anemia who were treated by bone-marrow transplantation. In 19 patients thyroxine declined sharply after bone-marrow transplantation and was associated with a reduction of the serum thyrotropin in the 17 patients tested, often to levels below the normal range. The serum triiodothyronine level, free thyroxine index, and free thyroxine level also declined in these patients. In the patients who recovered, clinical improvement was accompanied by the return of thyrotropin and thyroid hormone concentrations to their pretreatment ranges. These and related findings suggest that the low-thyroxine state of severe illness is the result of several events, one of which is failure of the normal negative-feedback control of the pituitary-thyroid axis due to illness-associated, decreased secretion of thyrotropin. The notion that such patients are "euthyroid" must be questioned, but the possible value of thyroid hormone-replacement therapy in these circumstances remains to be determined.

For many years the thyroid was thought to be involved in the decrease of basal metabolic rate that accompanies advancing age. Although recent evidence suggests that the change in oxygen consumption may merely reflect a decrease in "metabolic mass" (1), the advent of radioisotope techniques and methods for measuring the level of thyroid hormone in blood led to the hope that new information bearing on the role of the thyroid might become available. We have reviewed the investigations of others and presented our own results in previous publications dealing with the relationship of age to serum protein-bound iodine (PBI) and the thyroidal accumulation of radioiodide in euthyroid man (2, 3). The data suggest that the PBI does not change, but that radioiodide accumulation and thyroidal plasma radioiodide clearance decrease with age.Unfortunately, the radioiodide data are difficult to interpret, since it is not possible to equate a decrease in the uptake of tracer radioiodide with a decrease in thyroid hormone formation (3). Moreover, although the statistical significance of the age-dependent decrease in uptake is clear, the scatter of the individual values is such that the magnitude of the change can be only approximated. Although clinically useful for studying the extremes of thyroid function, there is little evidence that the basal metabolic rate, the serum PBI, or the thyroidal uptake of radioiodide is closely related to the rate of thyroid hormone production in euthyroid man. None of the available studies, therefore, particularly clarifies the issue of whether thyroid activity changes with age.About ten years ago Riggs reviewed the methods available for estimating quantitatively the rate of thyroid hormone formation, but these have not been used in studies of the relationship of age to thyroid function (4). A few years later several investigators described the radiothyroxine turnover technique that permits quantitative estimation of thyroid hormone output in man (5, 6, 7). An important advantage of this method is that it also allows independent determinations of the thyroxine distribution space, pool size, and fractional turnover rate. We undertook the present study hoping to define the range of thyroid function in euthyroid man and the relationship of age both to over-all gland activity and these parameters of thyroid hormone utilization. A preliminary report of our results has been presented (8). METHODSIn general the methods used here have been described by Ingbar and Freinkel (6) and by Sterling and Chodos (7). Radioactive thyroxine labeled with I"31 was obtained from the Abbott Co. as a 50 per cent propylene glycol solution containing approximately 500 1uc per ml, with specific activity ranging from 20 to 40 mc per mg. Over the period of this study (from early 1957 to the middle of 1958) many thyroxine preparations were used. The thyroxine was administered within a few days to a week after receipt, although a few determinations were made with material as old as three weeks. Although the labeled material is ma...

Melatonin is produced not only by the pineal gland but by cells of the bone marrow. Moreover, melatonin is known to promote osteogenic differentiation in several cell line models and in multipotential bone marrow mesenchymal stem cells. Fatty acids have been independently shown to direct such cells to acquire the phenotype and molecular characteristics of adipocytes. To examine the effect of melatonin on intracellular triglyceride accumulation, an indicator of adipogenic differentiation in the rat osteoblast-like ROS17/2.8 cell line, cells were incubated with added oleic acid (100 muM), fixed and stained with Oil Red O. Cellular lipid accumulation was quantitated by an Oil Red O method highly specific for triglycerides and expressed as a triglyceride accumulation index (TGAI, triglyceride per cell). Melatonin in nanomolar concentrations inhibited oleic acid-induced triglyceride accumulation. To identify the mechanism by which melatonin reduces triglyceride accumulation, cells were incubated with the two melatonin receptor antagonists, luzindole and S20928, or forskolin, a stimulator of adenylyl cyclase and cAMP production. These compounds prevented the inhibitory effect of melatonin on triglyceride accumulation, indicating that melatonin acts through known melatonin receptor-mediated mechanisms. In view of the previously demonstrated positive effects of melatonin in promoting osteoblastic differentiation in ROS17/2.8 cells and their reciprocal adipocytic differentiation induced by fatty acids, our observations may serve to relate the known age-related decreases of melatonin production, the shift in the bone marrow toward an adipocytic line of cell development, and the development of osteoporosis during aging.

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