The original concept of the critical period of thyroid hormone (TH) action on brain development was proposed to identify the postnatal period during which TH supplement must be provided to a child with congenital hypothyroidism to prevent mental retardation. As neuropsychological tools have become more sensitive, it has become apparent that even mild TH insufficiency in humans can produce measurable deficits in very specific neuropsychological functions, and that the specific consequences of TH deficiency depends on the precise developmental timing of the deficiency. Models of maternal hypothyroidism, hypothyroxinaemia and congenital hyperthyroidism have provided these insights. If the TH deficiency occurs early in pregnancy, the offspring display problems in visual attention, visual processing (i.e. acuity and strabismus) and gross motor skills. If it occurs later in pregnancy, children are at additional risk of subnormal visual (i.e. contrast sensitivity) and visuospatial skills, as well as slower response speeds and fine motor deficits. Finally, if TH insufficiency occurs after birth, language and memory skills are most predominantly affected. Although the experimental literature lags behind clinical studies in providing a mechanistic explanation for each of these observations, recent studies confirm that the specific action of TH on brain development depends upon developmental timing, and studies informing us about molecular mechanisms of TH action are generating hypotheses concerning possible mechanisms to account for these pleiotropic actions.

http://www.bio.umass.edu/biology/zoeller/pdf/JNeuroendo.pdf

Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings.

Background Transient hypothyroxinemia, a common finding in premature infants, is not thought to have long-term sequelae or to require treatment. We investigated whether hypothyroxinemia in premature infants is a cause of subsequent motor and cognitive abnormalities. Methods In this historical cohort study, we retrieved blood thyroxine values, obtained on routine screening in the first week of life, from state screening records of children who weighed 2000 g or less at birth, who were born at 33 weeks' gestation or earlier, and who were enrolled in a population-based study of the late sequelae of neonatal brain hemorrhage. We investigated the relation of these values to the odds for disabling cerebral palsy among 463 subjects for whom data were available and to the mental-development score on the Bayley Scales of Infant Development or the Stanford–Binet Intelligence Scales for Children at the age of two years in 400 subjects. The effects of severe hypothyroxinemia, defined as a blood thyroxine value more t...

https://www.nejm.org/doi/pdf/10.1056/NEJM199603283341303

The Relation of Transient Hypothyroxinemia in Preterm Infants to Neurologic Development at Two Years of Age

This article reviews the thyroid system, mainly from a mammalian standpoint. However, the thyroid system is highly conserved among vertebrate species, so the general information on thyroid hormone production and feedback through the hypothalamic-pituitary-thyroid (HPT) axis should be considered for all vertebrates, while species-specific differences are highlighted in the individual articles. This background article begins by outlining the HPT axis with its components and functions. For example, it describes the thyroid gland, its structure and development, how thyroid hormones are synthesized and regulated, the role of iodine in thyroid hormone synthesis, and finally how the thyroid hormones are released from the thyroid gland. It then progresses to detail areas within the thyroid system where disruption could occur or is already known to occur. It describes how thyroid hormone is transported in the serum and into the tissues on a cellular level, and how thyroid hormone is metabolized. There is an in-depth description of the alpha and beta thyroid hormone receptors and their functions, including how they are regulated, and what has been learned from the receptor knockout mouse models. The nongenomic actions of thyroid hormone are also described, such as in glucose uptake, mitochondrial effects, and its role in actin polymerization and vesicular recycling. The article discusses the concept of compensation within the HPT axis and how this fits into the paradigms that exist in thyroid toxicology/endocrinology. There is a section on thyroid hormone and its role in mammalian development: specifically, how it affects brain development when there is disruption to the maternal, the fetal, the newborn (congenital), or the infant thyroid system. Thyroid function during pregnancy is critical to normal development of the fetus, and several spontaneous mutant mouse lines are described that provide research tools to understand the mechanisms of thyroid hormone during mammalian brain development. Overall this article provides a basic understanding of the thyroid system and its components. The complexity of the thyroid system is clearly demonstrated, as are new areas of research on thyroid hormone physiology and thyroid hormone action developing within the field of thyroid endocrinology. This review provides the background necessary to review the current assays and endpoints described in the following articles for rodents, fishes, amphibians, and birds.

General Background on the Hypothalamic-Pituitary-Thyroid (HPT) Axis

The adequate functioning of both the maternal and fetal thyroid glands play an important role to ensure that the fetal neuropsycho-intellectual development progresses normally. Three sets of clinical disorders are considered, that may eventually lead to impaired brain development. Firstly, in infants with a defect of glandular ontogenesis (congenital hypothyroidism), the participation of maternal thyroid hormones to the fetal circulating thyroxine environment is normal and, therefore, risk of brain damage results exclusively from the insufficient hormone production by the abnormal fetal thyroid gland. Secondly, when it is only the maternal thyroid gland that is functionally deficient (autoimmune hypothyroidism), the severity and temporal occurrence of maternal underfunction will both drive the resulting consequences for impaired fetal neuronal development. Clinical situations of this type may obviously take place already during early gestation (in women with known but untreated hypothyroidism) or appear only during later gestational stages (in women who have AITD and remain euthyroid during the first half of gestation). Lastly, in conditions with iodine deficiency, both maternal and fetal thyroid functions are affected and, therefore, it is primarily the degree and precocity of the maternal hypothyroxinemia due to iodine deficiency during pregnancy that will drive the potential repercussions for fetal neurological development. In the present review, we summarize available data and develop our present concepts concerning the complex feto-maternal thyroid relationships and the potential impacts of thyroid function abnormalities on the ideal development of the offspring.

The Potential Repercussions of Maternal, Fetal, and Neonatal Hypothyroxinemia on the Progeny

Thyroid hormone is essential for normal brain development. Therefore, it is a genuine concern that thyroid function can be altered by a very large number of chemicals routinely found in the environment and in samples of human and wildlife tissues. These chemicals range from natural to manufactured compounds. They can produce thyroid dysfunction when they are absent from the diet, as in the case of iodine, or when they are present in the diet, as in the case of thionamides. Recent clinical evidence strongly suggests that brain development is much more sensitive to thyroid hormone excess or deficit than previously believed. In addition, recent experimental research provides new insight into the developmental processes affected by thyroid hormone. Based on the authors' research focusing on the ability of polychlorinated biphenyls to alter the expression of thyroid hormone-responsive genes in the developing brain, this review provides background information supporting a new way of approaching risk analysis of thyroid disruptors.

https://www.env.go.jp/chemi/end/sympo/2001/report/pdf_e/zoeller_e.pdf

Jaap J. van der Meere

Papers

Motor and cognitive-development in children with congenital hypothyroidism - a long-term evaluation of the effects of neonatal treatment