Rats were injected with monosodium 1-glutamate (MSG) daily for the 1st 5 days of life and allowed to mature. This is known to cause selective destruction of neurons in the retina and in the arcuate nucleus of the hypothalamus. The adult animals had a significant increase in body fat without an increase in weight, a marked reduction in pituitary, thyroid, adrenal, gonadal and prostate weights. Pituitary, hypothalamic and serum thyrotropin (TSH) were significantly reduced in the males. Serum growth hormone (GH) was markedly reduced in both sexes and the serum prolactin (Prl) was increased significantly in females. FSH did not appear to be abnormal and the LH may have been increased in the males. Serum T₄ was significantly reduced in females. The fertility of the females was normal, but treated males mated with normal females showed a marked reduction in fertility and, although the litter sizes of the offspring were normal, the birth weights of the pups of both sexes were significantly reduced. These persistent alterations in neuroendocrine function indicate that lesions produced by neonatal MSG treatment provide a convenient model for studying hypothalamic function.

Rats made thyrotoxic with large doses of thyroxine (T4) during the neonatal period (neo-T4) show many abnormalities as adults. These usually include impaired body, pituitary and thyroid growth, diminished pituitary and serum TSH concentrations, a diminished serum T4 and a diminished response to PTU challenge and to thyrotropin-releasing hormone (TRH) stimulation. Experiments are presented which show that these rats are hypersensitive to feedback regulation by T4 in a manner similar to that seen after bilateral anterior hypothalamic lesions. They show a subnormal response to PTU challenge and an excessive suppression of serum TSH and goiter growth after T4. Pituitary TSH was less depleted in neo-T4 rats when a small dose of T4 was given daily with PTU and pituitary TSH was more sensitive to suppression by a larger dose of T4 in the neo-T4 group. There was an impaired rebound increase in pituitary TSH following a single inhibitory dose of T4 injected into the adult hypothyroid rat. Although the hypothalamic TRH content is increased in the neo-T4 rat, the circulating concentration of TRH was found to be significantly decreased, supporting the theory that the defects observed in the neo-T4 rat may be the consequence of an impaired hypothalamic secretion of TRH.

When neonatal rats are made hyperthyroid with large doses of thyroxine during the first 5 days of life, they develop hypothalamopituitary, thyroidal and gonadal abnormalities that persist through life. When female rats, which have been treated neonatally, are subsequently mated to normal males, their offspring show unexpected gonadal and thyroidal defects, such as reduced weaning weight and delayed vaginal opening and first estrus in females; males show a significant increase in relative thyroid weight and a significant decrease in ventral prostate weight. Cross-fostering was done to separate prenatal from postnatal influences. Even more surprising was the finding that when the untreated female F₁ progeny were mated with normal males, the untreated F₂ progeny showed more defects and to a greater degree than those present in the maternal parent.

No abstract

ExtractExperiments were conducted to assess late and persistent endocrine changes in the progeny of rats born of and/or nursed by thyroidectomized ( T x ) dams. Forty-five female rats were radiothyroidectomized several weeks before mating with normal males, and compared with the progeny of 26 control females. In all, 248 progeny were studied when adult.T x dams had significantly reduced fertility (87% of controls), increased pup (11% versus 0) and maternal mortality (27% versus 0), and smaller litters (6.5 versus 11.8 pups/litter). It was shown that the offspring of thyroidectomized female rats had delayed eye opening (15.3 versus 14.3 days), smaller weaning (40.4 versus 54.4 g ) and adult body weights (230 versus 260 g), smaller pituitary glands (12.2 versus 14.0 mg), and enlarged thyroid glands (14.2 versus 12.4 mg). Ovarian and testicular weights were decreased (73.9 versus 83.7 mg and 3.2 versus 3.6 g, respectively). The serum thyroid stimulating hormone ( T S H ) concentrations were increased from 53.8 to 84.4 wU/ml in the males. The pituitary T S H contents were not significantly altered, and the serum T S H response to thyrotropin releasing hormone ( T R H ) was normal. These persistent effects differed from the late effects of both fetal and neonatal hypothyroidism and neonatal underfeeding. Cross-fostering experiments showed that the diminished weaning weights were the result of the pups being nursed by the hypothyroid dams. The increased nursing mortality and the pituitary and thyroidal changes were the result of prenatal influences produced by the hypothyroid dams, since being nursed by a normal foster dam did not prevent them. The persistently enlarged thyroid glands and the elevated serum T S H in the male offspring of thyroidectomized dams suggested a permanent alteration in the set point of pituitary-thyroid regulation as the consequence of maternal hypothyroidism. SpeculationIt is speculated that the intrauterine environment provided by the pregnant hypothyroid mother produces permanent alterations in endocrine regulatory mechanisms in the offspring. It is suggested that the transplacental transfer of fetal thyroxine (T,) to the hypothyroid mother places a burden on the fetal pituitary-thyroid axis that permanently alters its function in these progeny. W e have shown previously that during a critical perinatal period, T , excess or deficiency can permanently alter hypothalamo-pituitary regulatory function in the offspring.Whether or not maternal hypothyroidism can cause fetal or congenital hypothyroidism has been an enigma for many years. It has been stated that if a woman has given birth to two cretins she has an increased chance of producing a cretin in the next pregnancy (10). However, even severely hypothyroid mothers usually deliver normal infants (21), and most mothers of cretins are euthyroid throughout their pregnancy. For these reasons, it has been necessary to consider other explanations for the sporadic congenitally hypothyroid infant. Current theory proposes that genetic factors may p...