Transformation of Normal Follicles into Thyrotropin-Refractory “Cold” Follicles in the Aging Mouse Thyroid Gland*

Abstract

Autoradiographs of thyroid glands of aging mice demonstrate the gradual appearance of "cold" follicles which fail to iodinate the intraluminar iodoproteins even after intense exogeneous or endogeneous TSH stimulation. "Cold" follicles first appear at the age of 5 months. They may account for 80% of all thyroid follicles in 13-month-old mice. Morphologically, the "cold" follicles are characterized by a larger than normal colloid volume and a comparatively flat epithelium for any given follicle size. Old thyroids are twice as large as young ones. They contain twice as much normally iodinated thyroglobulin/mg wet weight. The total number of cells per gland remains constant throughout the life time. This is probably also true for the total number of follicles. The iodide pump, as judged by the tissue to serum ratio, remains normal and TSH-responsive. Yet, it is not established whether this is due to a higher activity of the pump in normal follicles or to preservation of inorganic iodide transport in "cold" follicles. Pinocytosis is defective in "cold" follicles and is poorly responsive to TSH stimulation. Furthermore, diffusion of iodocompounds is severely impaired in the colloid of "cold" follicles. It is suggested that the primary defect in the pathogenesis of "cold" follicles in old mice is the gradual failure of endocytosis to respond to normal TSH stimulation. Because exocytosis and iodination would first proceed normally, the follicular lumina would become overdistended up to a point where the apical membrane is functionally impaired. With this sequence of events, "cold" follicles would have impaired iodination while being metabolically as active as hot ones. Thus, several puzzling reports on high metabolic activity of "cold" tissue could possibly be interpreted.

Evidence for co-ordinated changes between vascular endothelial growth factor and nitric oxide synthase III immunoreactivity, the functional status of the thyroid follicles, and the microvascular bed during chronic stimulation by low iodine and propylthiouracyl in old mice

“…In the thyroid of old mice, two types of follicles coexist ('hot' and 'cold' follicles) (21)(22)(23) that reflect the tendency of the thyroid to form multinodular goiter. Based on 125 I autoradiographic studies (21)(22)(23), slowly functioning follicles are characterized by delayed organification and iodine release.…”

“…Follicles were ranked as 'cold' or 'hot' depending on the aspect of their epithelium and their colloid, according to previous autoradiography studies (21)(22)(23). Variation of the microscopical aspects correlated with various functional states.…”

“…This heterogeneity can be enhanced, leading to the formation of non or poorly functional follicles named hereby 'cold' follicles that can cluster to form 'cold' nodules. The presence of 'cold' follicles in the thyroid gland of old mice makes them a model of nodule formation (21)(22)(23). These follicles could result from local differences in the functional status of their cells and/or of their microvascular bed.…”

Fine structural aspects on the cold follicles in the aged mouse thyroid.

“…Recently, using the autoradiographic technique of light microscopic level, STUDER et al (1978) reported that "cold" follicles which appear in the normal mouse thyroid with advancing age, account for 80% of all thyroid follicles in 13-month-old female mice. The present authors wish to use the term "cold" follicle to describe the type of the follicle which dose not respond to intensive injections of exogenous TSH, lacking an ability to accumulate iodine into the follicular lumen.…”

Does amiodarone affect heart rate by inhibiting the intracellular generation of triiodothyronine from thyroxine?

“…Iodine Iodine was determined in heart and liver according to Lauber (1975), a method which has been used in this laboratory for previous studies (Studer et al, 1978;Staubli etal., 1983). In principle, determination of iodine is based on incineration of organic material followed by the redox reaction 2 CerNv + Asm = 2 Cer"' + Asv, which is catalyzed by iodide and which can be measured by photometric absorption.…”