A level of thyroid hormone (TH) in agreement with the tissue requirements is essential for vertebrate embryogenesis and fetal maturation. In this study we evaluate the immediate and long-term effects of incongruent intrauterine TH levels between mother and fetus using the TH receptor (TR) beta(-/-) knockout mouse as a model. We took advantage of the fact that the TRbeta(-/-) females have elevated serum TH but are not thyrotoxic due to resistance to TH. We used crosses between heterozygotes with wild-type phenotype (TRbeta(+/-)) males and TRbeta(-/-) females, with a hyperiodothyroninemic (high T(4) and T(3) levels) intrauterine environment (TH congruent with the TRbeta(-/-) fetus and excessive for the TRbeta(+/-) fetus), and reciprocal crosses between TRbeta(-/-) males and TRbeta(+/-) females, providing a euiodothyroninemic intrauterine environment. We found that TRbeta(-/-) dams had reduced litter sizes and pups with lower birth weight but preserved the mendelian TRbeta(-/-) to TRbeta(+/-) ratio at birth, indicating that the incongruous TH levels did not decrease intrauterine survival of a specific genotype. The results of studies in newborns demonstrate that TRbeta(+/-) pups born to TRbeta(-/-) dams have persistent suppression of serum TSH without a peak. On the other hand, TRbeta(-/-) pups born to TRbeta(+/-) dams have lower serum TSH at birth and a tendency to peak higher, compared with TRbeta(-/-) pups born to TRbeta(-/-) dams. The studies in the adult progeny demonstrate that TRbeta(+/-) mice born to TRbeta(-/-) dams and, thus, exposed to higher intrauterine TH levels, have greater resistance to TH at the level of the pituitary when stimulated with TRH. On the other hand, TRbeta(-/-) mice born to TRbeta(+/-) dams and, thus, deprived of TH in uterine life, were more sensitive to TH when similarly stimulated with TRH. Thus, TH exposure in utero has an effect on the regulatory set point of the hypothalamus-pituitary-thyroid axis, which can be seen early in life and persists into adulthood.