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Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis- Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level.

T3 was injected daily in newborn rats from birth to 16 days of age. Control rats received daily injections of vehicle during the same period. The proliferative activity of the Sertoli cells was studied by means of bromodeoxyuridine incorporation, and tubular lumen formation and nuclear size were taken as markers of Sertoli cell differentiation. T3 treatment strongly reduced the proliferative activity of Sertoli cells from day 7 on, and on day 12, proliferation of Sertoli cells had ceased, while in control rats proliferating Sertoli cells were observed up to day 16. As a result of the reduced Sertoli cell proliferation, the final Sertoli cell number per testis at 23 days of age was reduced by 50% from 38 +/- 1 x 10(6) in control rats to 19 +/- 1 x 10(6) in T3-treated rats. Lumen formation in seminiferous tubules of T3-treated rats began at 12 days of age, while in controls lumen formation was first observed at 16 days. The area of the Sertoli cell nuclei was somewhat larger in T3-treated rats on day 16, but not at any other age examined. Body and testis weights in adult rats at 100 days of age were reduced by 46% and 48% of control values, respectively. The high neonatal T3 levels reduced serum levels of TSH on days 7 and 9, but not at any other age examined. FSH levels were reduced in T3-injected rats on days 5 and 7 and increased on day 23, after cessation of treatment. Immunoreactive inhibin-alpha levels were increased on days 5-9 and reduced on days 16 and 23. These findings indicate that T3 stimulates the production of immunoreactive inhibin by Sertoli cells, but also of bioactive inhibin, as indicated by the reduced FSH levels. It is concluded that the levels of thyroid hormones early in life are important for the terminal differentiation of Sertoli cells and, therefore, for determining adult testis size. The data indicate that this might be a direct effect of T3 on Sertoli cells.

In this study we show that 6-propyl-2-thiouracil (PTU) treatment of Wistar rats from birth up to day 26 p.p. retards the morphological differentiation of Sertoli cells, and prolongs the proliferation of these cells up to day 30. Sertoli cell numbers per testis, determined at day 36, were increased by 84% compared to controls. PTU treatment increased serum thyroid-stimulating hormone (TSH) levels and reduced serum levels of thyroxine (T4) from 5 days onwards, indicative of severe hypothyroidism. Follicle-stimulating hormone (FSH) levels were reduced from day 5 to 9, normal at day 12 and 16, and reduced again from day 20 to 36. Inhibin levels were decreased from day 9 to 20 and increased at 36 days of age. The increase in the number of Sertoli cells per testis in PTU treated rats, as has been reported in the present study, is likely to be responsible for the increased testis size observed by other groups (1) in these animals, when adult.

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