Treatment of ovine cretinism in utero with 3,5-dimethyl-3'-isopropyl-L-thyronine.
Placental transfer of iodothyronines is minimal in most species. The nonhalogenated thyroid hormone analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) was administered to pregnant ewes to determine if this compound could prevent cretinism in the thyroidectomized fetal lamb. Pharmacokinetic studies comparing [125I]T3 and [3H]DIMIT resulted in fetal-maternal ratios for [3H]DIMIT which were 5- to 10-fold higher than the ratios for [125I]T3, suggestive of preferential transport of DIMIT across the placenta. Subsequently, DIMIT was administered to three pregnant ewes after hysterotomy and fetal thyroidectomy at 95-98 days gestation. Intramuscular DIMIT (1200-2000 micrograms/day) caused suppression of maternal T4 concentrations from a mean of 4.9 micrograms/dl before hysterotomy to less than 1 micrograms/dl within 1-2 weeks. All three thyroidectomized lambs had clinical signs of cretinism at birth and died. Skeletal and lung maturation were delayed in these animals, all of whom had undetectable serum T4 concentrations. In contrast to DIMIT's proven thyromimetic activity in other fetal animal models, this thyroid hormone analog failed to prevent cretinism in thyroidectomized fetal lambs even when administered to the ewe at a dose that suppressed maternal thyroid function.
D000818:Animals; D003409:Congenital Hypothyroidism / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy*; D007700:Kinetics; D011247:Pregnancy; D012756:Sheep; D013965:Thyroidectomy; D013970:Thyronines / Q000378:metabolism / Q000627:therapeutic use*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D013970:Thyronines; D014284:Triiodothyronine; C022861:3,5-dimethyl-3'-isopropyl-L-thyronine; D013974:Thyroxine