Thyroid Gland Function in Normal Physiology
Primary Regulatory Mechanism
The thyroid gland functions through a tightly controlled feedback loop where the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the pituitary to secrete thyroid-stimulating hormone (TSH), which in turn drives the thyroid gland to produce and release thyroid hormones T4 and T3. 1
The hypothalamic-pituitary-thyroid axis operates as the central control system, with TRH playing a dominant role in regulating this axis—more significant than previously understood 1. When circulating thyroid hormone levels drop, the hypothalamus increases TRH production, which cascades through the system to restore hormone balance 1.
Thyroid Hormone Synthesis and Storage
The thyroid gland contains numerous follicular cells that store thyroid hormones within thyroglobulin molecules until the body requires them 2. TSH regulates multiple critical steps in hormone production 3:
- Stimulation of iodide uptake from the bloodstream into thyroid follicular cells 3
- Activation of thyroid peroxidase enzyme, which catalyzes key reactions in hormone synthesis 3
- Regulation of iodide oxidation and organification, where iodine is incorporated into tyrosine residues 3
- Control of T4 and T3 secretion into the circulation 3
Adequate iodine intake is essential, with adults requiring 150 μg/day for proper thyroid hormone synthesis 3. The synthesis process depends on both iodine and the amino acid tyrosine as building blocks 2.
Negative Feedback Regulation
Thyroid hormones exert negative feedback at both the hypothalamic and pituitary levels 1. When T4 and T3 levels rise, they inhibit TRH gene transcription in the hypothalamus and TSH subunit gene transcription in the pituitary 1. This feedback also affects posttranslational modification and release of TSH 1. The thyroid hormone receptor ligand-dependent activation function (AF-2) domain plays an unanticipated role in this negative regulation 1.
Hormone Transport and Cellular Uptake
Once released into circulation, thyroid hormones—primarily T4 (thyroxine) and T3 (tri-iodothyronine)—must enter target cells to exert their effects 4. Saturable transport mechanisms mediate the majority of thyroid hormone movement across plasma membranes 4.
System L1 permease transports thyroid hormones and amino acids in adipose tissue, placenta, and brain 4. T3 is also transported by System T, which shows selectivity for aromatic amino acids 4. The activity of these transporters determines both cellular hormone sensitivity and responses to changes in circulating hormone concentrations 4.
Metabolic Actions
Thyroid hormones regulate growth, differentiation, development, and metabolic homeostasis by controlling gene expression through thyroid hormone receptors (TRs) in the nucleus 5. The major target tissues include the brain, liver, muscle, heart, and adipose tissue 6.
Thyroid hormones affect virtually every cell in the body and are considered the major metabolic hormones 2. They increase metabolic rate in hyperthyroidism and decrease it in hypothyroidism 3. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and cellular location of TRs 5.
Nutritional Cofactors
Beyond iodine, other nutrients are crucial for proper thyroid function 3:
- Iron deficiency impairs thyroid metabolism, affecting the conversion and utilization of thyroid hormones 3
- Selenium is required for deiodination of T4 to T3 via the selenoenzyme Type 1 5'-deiodinase 3
Diagnostic Assessment
TSH serves as the primary screening test for thyroid function, with sensitivity above 98% and specificity greater than 92% 3. However, TSH levels alone are not sensitive indicators of iodine status, as concentrations usually remain within normal range despite frank iodine deficiency 3.
Free T4 and T3 measurements provide additional information about thyroid status and are used in conjunction with TSH levels to comprehensively assess thyroid function 3. Normal thyroid function is characterized by TSH values between 0.45-4.5 mIU/L with normal free T4 levels 7.