Hypothyroidism and Autism: Potential Brain Development Links

Researchers have long explored factors influencing brain development, particularly in conditions like autism spectrum disorder (ASD). One emerging area of interest is thyroid hormones, which are essential for early neurodevelopment. Disruptions in thyroid function during pregnancy or early life may contribute to atypical brain development, raising questions about potential links between hypothyroidism and ASD.

Understanding how thyroid function interacts with neurological pathways could provide insights into autism risk factors. Researchers are also examining genetic variations and autoimmune conditions that might influence both thyroid regulation and neurodevelopment.

Thyroid Hormones and Fetal Neurodevelopment

Thyroid hormones play a crucial role in fetal brain development, particularly during gestation when the fetal thyroid gland is not yet fully functional. During the first trimester, the fetus relies entirely on maternal thyroid hormones, primarily thyroxine (T4), which crosses the placenta and is converted into the bioactive triiodothyronine (T3) within fetal tissues. This hormonal supply is essential for neuronal proliferation, migration, and differentiation—processes that establish the structural and functional framework of the central nervous system. Disruptions in maternal thyroid function, including hypothyroidism or subclinical thyroid dysfunction, have been linked to altered cortical development, changes in synaptic plasticity, and cognitive deficits, raising concerns about their role in neurodevelopmental disorders like ASD.

One well-documented effect of thyroid hormone deficiency during pregnancy is impaired neuronal migration, which ensures neurons reach their appropriate locations in the developing brain. Studies using human epidemiological data and animal models have shown that insufficient thyroid hormone levels can lead to disorganized cortical layering, particularly in the prefrontal cortex and hippocampus—regions implicated in social cognition and executive function. A 2020 study in JAMA Pediatrics found that children born to mothers with untreated hypothyroidism had a significantly higher likelihood of ASD, suggesting that even mild disruptions in thyroid hormone availability during gestation may have lasting neurodevelopmental consequences.

Beyond structural development, thyroid hormones regulate genes involved in synaptogenesis and neurotransmitter balance, both critical for functional brain connectivity. Experimental research has shown that deficiencies in these hormones can alter the expression of genes related to gamma-aminobutyric acid (GABA) and glutamate signaling, two neurotransmitter systems frequently implicated in ASD. A 2019 meta-analysis in Molecular Psychiatry highlighted that disruptions in these pathways could contribute to the excitatory-inhibitory imbalance observed in autistic individuals, reinforcing the hypothesis that thyroid hormone insufficiency may play a role in atypical neurodevelopment.

Neuroendocrine Mechanisms Linking Thyroid Function and Neurological Pathways

Thyroid hormones influence brain function through endocrine signals and neural circuits. These hormones regulate neuronal activity by modulating gene expression, neurotransmitter systems, and synaptic organization. One primary mechanism is their interaction with nuclear thyroid hormone receptors (THRs), widely distributed throughout the brain. THRs function as transcription factors controlling genes involved in neuronal differentiation, axonal growth, and synaptic plasticity. Dysregulation of these receptors, whether due to insufficient hormone availability or receptor mutations, can lead to disruptions in neural connectivity, potentially contributing to ASD.

Thyroid hormones also affect neurotransmitter systems. Research has shown that T3 plays a role in regulating serotonin and dopamine signaling, neurotransmitters critical for mood regulation, social behavior, and cognitive function. A 2021 study in Translational Psychiatry found that altered thyroid hormone levels during early development correlated with atypical serotonin receptor expression in brain regions associated with social communication, a core feature of ASD. Additionally, thyroid hormones help maintain the balance between excitatory and inhibitory neurotransmission, particularly through their effects on GABA and glutamate pathways. Experimental models have demonstrated that thyroid hormone deficiencies can reduce GABAergic inhibition, contributing to the hyperexcitable neural circuits frequently observed in autistic individuals.

Thyroid hormones are also essential for myelination, the process by which oligodendrocytes form the myelin sheath around axons to facilitate efficient neural transmission. Proper myelination is necessary for coordinated neural signaling, and disruptions in this process have been linked to cognitive and behavioral impairments. Studies have shown that thyroid hormone deficiencies during critical periods of brain development result in delayed or abnormal myelination patterns, particularly in the corpus callosum and other white matter structures. These alterations may contribute to the atypical neural connectivity patterns observed in ASD, as neuroimaging studies have reported differences in white matter integrity among autistic individuals.

Genetic Variations Affecting Thyroid Regulation

Thyroid hormone regulation is controlled by a network of genes that influence hormone synthesis, transport, and receptor activity. Variations in these genes can affect hormone availability, potentially altering neurodevelopmental trajectories. One well-studied genetic contributor is the DIO2 gene, which encodes the enzyme deiodinase type 2. This enzyme converts the prohormone T4 into the biologically active T3, ensuring adequate thyroid signaling in tissues. Polymorphisms in DIO2 have been linked to altered T3 levels in the brain, which may affect cognitive function and neural plasticity. A 2018 genome-wide association study (GWAS) in Nature Communications identified a specific DIO2 variant associated with reduced enzymatic activity, leading to lower intracellular T3 concentrations. This finding raises questions about whether such genetic variations could predispose individuals to neurodevelopmental conditions, including ASD.

Genes involved in thyroid hormone transport also shape brain development. The MCT8 gene encodes monocarboxylate transporter 8, a protein critical for cellular T3 uptake. Mutations in MCT8 result in Allan-Herndon-Dudley syndrome, a rare neurodevelopmental disorder characterized by severe intellectual disability and motor impairments. While distinct from ASD, milder MCT8 polymorphisms have been investigated for their potential role in cognitive and behavioral differences. Impaired thyroid hormone transport into neurons could disrupt synaptogenesis and axonal outgrowth, fundamental to neural circuit development. The extent to which common MCT8 variants influence ASD susceptibility remains under investigation, but their role in thyroid hormone homeostasis suggests a plausible link.

Receptor function is another key aspect of thyroid hormone signaling. The THRB gene encodes thyroid hormone receptor beta (THRβ), one of the primary receptors mediating T3 action in the brain. Mutations in THRB can lead to resistance to thyroid hormone (RTH), a condition in which tissues fail to respond appropriately to circulating thyroid hormones. Individuals with RTH often display cognitive and behavioral symptoms, including attention deficits and social difficulties, which overlap with some ASD traits. Research suggests that even subclinical THRB variations could influence neural responsiveness to thyroid hormones, potentially contributing to differences in neurodevelopmental outcomes. Given the complexity of thyroid hormone signaling, multiple genetic variants likely interact to shape susceptibility to developmental conditions.

Co-Occurring Autoimmune Factors

Autoimmune conditions frequently intersect with thyroid dysfunction, raising questions about their role in neurodevelopmental disorders such as ASD. Hashimoto’s thyroiditis, the most common cause of hypothyroidism, is an autoimmune disorder characterized by antibodies targeting thyroid peroxidase (TPO) and thyroglobulin. These antibodies impair thyroid hormone production, leading to systemic hormonal imbalances. Epidemiological studies have found elevated rates of maternal thyroid autoimmunity in pregnancies where children later receive an ASD diagnosis, suggesting that immune-mediated thyroid dysfunction may influence early brain development.

Maternal thyroid autoantibodies can cross the placenta and interfere with fetal thyroid function, even when maternal hormone levels appear normal. This phenomenon has been observed in other autoimmune conditions, such as neonatal lupus, where maternal autoantibodies affect fetal tissues despite the absence of overt maternal symptoms. Some researchers hypothesize that thyroid autoantibodies may interact with fetal neural structures or disrupt thyroid hormone signaling in utero, leading to subtle but lasting changes in brain organization. A 2022 analysis in Endocrinology found that children born to mothers with elevated TPO antibodies exhibited differences in cortical thickness and connectivity patterns, reinforcing the idea that maternal thyroid autoimmunity may contribute to altered neurodevelopmental trajectories.