Mice with hereditary muscular dystrophy have reduced levels of serum T3. To determine possible causes of T3 deficits, we evaluated pituitary thyrotroph ultrastructure by electron microscopy, thyroid gland morphology by light microscopy, and T4 to T3 conversion by measuring iodothyronine 5'-deiodinase activity. Differences were not evident between dystrophic and normal littermates in either the structure of pituitary thyrotrophs or thyroid tissues. Dystrophic mice, however, had only 50% the normal hepatic 5'-deiodinase activity. Cerebral 5'-deiodinase, which does not appear to contribute significantly to serum T3, was similar in normal and dystrophic mice. Submandibular gland concentrations of nerve growth factor and epidermal growth factor are reduced in dystrophic mice but can be increased by T4 treatment. To distinguish whether growth factor deficits are due to reductions in serum T3 or to deficiencies in T4 5'-deiodinase activity and subsequent T3 utilization within the salivary gland, we measured submandibular deiodinase activity. Gland homogenates were active in the deiodinase assay, but no differences were detected between normal and dystrophic mice. In order to evaluate tissue responses to reductions in circulating T4, we treated mice with methimazole. Structural analyses revealed that thyrotrophs in dystrophic mice were less stimulated than thyrotrophs in similarly treated normal littermates. Likewise, thyroid follicular cells appeared less active, and thyroid weights increased only 40-50% as much as in normals. Liver 5'-deiodinase activity decreased in both normal and dystrophic mice. Cerebral 5'-deiodinase activity increased more than 4-fold in normal females but only 2-fold in dystrophic females; 2- to 3-fold increases occurred in both normal and dystrophic males. In summary, the structure of pituitary and thyroid glands in dystrophic mice is similar to that of tissues from normal littermates, but hepatic conversion of T4 to T3 is reduced. When challenged by methimazole-induced reductions in serum T4, pituitary and cerebral tissues in dystrophic mice respond abnormally.