The aim of this paper is to summarize some of our quantitative descriptive and experimental studies, to discuss them in view of the literature data, and to present a synthesis of the topic. The results of stereological analysis of some tissue components of the rat thyroid gland have been compared with the results of topological studies on the parafollicular cells of various mammalian species. Localization of the parafollicular cells in the central regions of the thyroid gland lobes, where the follicular cell activity seems to be greater than in the periphery of the lobes, has led to the hypothesis that the parafollicular cells regulate (stimulate and/or suppress) the activity of the follicular cells. Long-term application and antithyroid drugs to mice and rats has shown that excessive concentrations of thyrotropin provoke hyperplasia of both the follicular cells and the intrathyroid mast cells and, transiently, of the parafollicular cells. This and some of the literature data are congruent with the hypothesis that the parafollicular and mast cells also stimulate the follicular cells by their paracrine secretions. Long-term application of antithyroid drugs to mice and rats has shown that excessive concentrations of cular cells but also probably stimulation of the follicular cells, as judged by the stereological measurements. The biological meaning of the spatial integration of follicular and parafollicular cells seems to be a functional coordination of both epithelial cell lines, supported by intrathyroid mast cells.

SUMMARY A histometric thyroid gland activation index has been proposed as a quotient between the mean voluminal percentage of the epithelial cells and the colloid. A positive correlation between the blood TSH level and this index is supposed.

In three experiments of 30 weeks' duration, 93 adult female Wistar rats received controlled amounts of calcium with food and water, to produce a state of either hypercalcemia or hypocalcemia. A systematic stereological analysis of the thyroid glands and a radioimmunological analysis of thyroxine, triiodothyronine, and thyrotropine were performed. In the hypercalcemic rats, a reactive hyperplasia of the parafollicular cells was established; this was accompanied by morphological and biochemical signs of hyperfunction of the follicular cells, despite a reduced central stimulation by thyrotropin. In the hypocalcemic animals, no quantitative morphological changes in the parafollicular cells were observed; however, morphological and biochemical signs of hypofunction of the follicular cells were obvious, despite stronger central stimulation by thyrotropin. It is concluded that the extrinsic regulation of follicular cells by the blood calcium level is stronger than the intrinsic regulation by hypothalamo-hypophyseal hormones.

The average thickness of the thyroid epithelial cells may be determined either directly or indirectly. By the direct or caliper method, this thickness is overestimated as a result of which its empirical value must be divided by a correction factor Kd. By the indirect method, on the other hand, the thickness of the thyroid gland epithelium is calculated as the ratio of the double volume density of the epithelium to the sum of the inner and the outer surface density of the epithelium; in this case the sought for thickness value is underestimated and must consequently be multiplied by a factor Ki.Both correction factors are algebraically defined. Their values are calculated and graphically represented as a function of the thyroid activation index (the ratio between the volume density of the epithelium and the colloid) for the range from 0.1 to 100.The validity of the theoretical interpretation of the discrepancy between the values obtained for the average thickness of the thyroid epithelium by the direct and the corresponding values obtained by the indirect method, is empirically tested. It is shown that by the introduction of appropriate correction factors the difference between the results obtained by each method can be reduced. These improved direct and indirect methods for determining the wall thickness of a hollow sphere seem to lend themselves to being used in the stereological analysis of other biological, perhaps even non-biological materials of similar structure. THE P R O B L E MIn order to estimate the functional state of the thyroid the average thickness of epithelial cells in the wall of thyroid follicles is determined. This can be done either directly by measuring the apparent cell thickness on sections, or by an indirect method from the volume-to-surface ratio of the epithelium. The former method however yields, as a rule, higher values than the latter one. The present paper deals with the reasons for this discrepancy and offers some suggestions to avoid it. It is assumed that under physiological conditions the walls of thyroid follicles closely resemble hollow spheres. This assumption permits a geometrical analysis of the problem. lo** 157

In a 46-week-experiment on 72 female mice the influence of peroral 1.2% sodium perchlorate application, total ionizing irradiation with 8 Gy on 5 consecutive days and their interaction on the pituitary-thyroid axis was studied by histological and stereological methods. It was observed that perchlorate alone caused long-term and strong hypothyroidism with hypertrophic and hyperplastic thyroid epithelial cells as well as pituitary thyrotropic cells. When only irradiation was used, no uniform changes in the structure and function of these cells could be detected. The interaction of perchlorate and irradiation showed similar effects as thyrostatics alone, with some exceptions; paradoxically, minor hyperplasia of thyrotropic as well as of parafollicular cells was observed. A high percentage of the follicular cell carcinoma was found after perchlorate application and after its combination with irradiation. No medullary carcinoma was found.