Thyroxine, also known as T4, and triiodothyronine, or T3, are iodothyronines and important thyroid hormones. They are stored in the thyroid gland as part of the glycoprotein molecule thyroglobulin. These hormones have low solubility in blood and aqueous fluids and are mainly transported in the blood while bound to serum-binding proteins, with thyroid hormone-binding globulin being a major transport protein. Thyroxine has a half-life of 7 days, while triiodothyronine has a half-life of 18 hours. Similar to steroid hormones, thyroid hormones act intracellularly as transcription factors through the thyroid hormone receptor, which belongs to the same gene family as steroid hormone receptors and vitamin D receptor. Oral administration of thyroid hormones is effective due to sufficient absorption intact.

Hormones, including steroid and thyroid hormones, are transported in the blood either bound to plasma proteins or free. The liver regulates the production of plasma transport proteins that bind a significant fraction of these hormones in blood. Protein and polypeptide hormones, on the other hand, are generally transported freely in the blood. The concentrations of free hormone, bound hormone, and plasma transport protein are in equilibrium. When the levels of free hormone decrease, hormone is released from the transport proteins according to the equilibrium relationship described by Equation 38.1. Free hormone is the biologically active form and plays a role in target organ action, feedback control, and cellular uptake and metabolism. Therefore, in hormonal status evaluation, it is sometimes necessary to determine free hormone levels in addition to total hormone levels. This is particularly important as hormone transport proteins are regulated by changes in endocrine and disease states.

Protein binding of hormones serves multiple purposes. It extends the circulating half-life of hormones and prevents rapid cellular uptake or kidney excretion for hormones that can cross cell membranes easily. Bound hormones act as a reservoir and buffer acute changes in hormone secretion. Additionally, protein binding facilitates the transport of hormones that are poorly soluble in blood, such as steroids.

Hormones, also known as ligands, bind to receptors and initiate cellular responses. Receptor antagonists block receptor activity, preventing cellular responses, while loss or inactivation of receptors leads to hormonal resistance. Constitutive activation of receptors results in unregulated, hormone-independent cellular processes.

Hormones play a vital role in regulating various cellular functions in all organ systems. They control cell growth, determining size and division capabilities. Hormones influence cell differentiation, survival, and programmed cell death. They impact cellular metabolism, the ionic composition of body fluids, and cell membrane potential. Hormones orchestrate complex cytoskeleton-associated events, including cell shape, migration, division, exocytosis, recycling/endocytosis, and cell-cell and cell-matrix adhesion. Hormones regulate the expression and function of cytosolic and membrane proteins, and they can affect the levels of their own receptors or the receptors for other hormones.
3,5,3˜5˜-Tetraiodothyronine (thyroxine, or T4) 3,5,3˜-Triiodothyronine (T3) •Fig. 38.11 Structureofthyroidhormones,whichareiodothyronines.
transport systems. They are stored extracellularly in the thyroid as an integral part of the glycoprotein molecule thyroglobulin. Thyroid hormones are sparingly soluble in blood and aqueous fluids and are transported in blood that is bound (>99%) to serum-binding proteins. A major transport protein is thyroid hormone–binding globulin. Thyroid hormones have long half-lives (7 days for thyroxine; 18 hours for triiodothyronine). Thyroid hormones are similar to steroid hormones in that the thyroid hormone receptor is intracellular and acts as a transcription factor. In fact, the thyroid hormone receptor belongs to the same gene family that includes steroid hormone receptors and vitamin D receptor. Thyroid hormones can be administered orally; the amount absorbed intact is sufficient for this to be an effective mode of therapy.
Transport of Hormones in the Circulation
A significant fraction of steroid and thyroid hormones is transported in blood that is bound to plasma proteins that are produced in a regulated manner by the liver. Protein and polypeptide hormones are generally transported free in blood. The concentrations of bound hormone, free hormone, and plasma transport protein are in equilibrium. If free hormone levels drop, hormone will be released from the transport proteins. This relationship may be expressed as follows:
Equation 38.1 where [H] = concentration of free hormone, [P] = concentration of plasma transport protein, [HP] = concentration of bound hormone, and K = the dissociation constant.
Free hormone is the biologically active form for action on the target organ, feedback control, and clearance by cellular uptake and metabolism. As a consequence, when hormonal status is evaluated, sometimes free hormone levels must be determined in addition to total hormone levels. This is particularly important because hormone transport proteins themselves are regulated by altered endocrine and disease states.
Protein binding serves several purposes. It prolongs the circulating half-life of the hormone. Many hormones cross cell membranes readily and would either enter cells or be excreted by the kidneys if they were not protein bound. The bound hormone represents a reservoir of hormone and, as such, can serve to buffer acute changes in hormone secretion. Some hormones, such as steroids, are sparingly soluble in blood, and protein binding facilitates their transport.
Cellular Responses to Hormones
Hormones are also referred to as ligands, in the context of ligand-receptor binding, and as agonists, in that their binding to the receptor is transduced into a cellular response. Receptor antagonists typically bind to a receptor and lock it in an inactive state, in which the receptor is unable to induce a cellular response. Loss or inactivation of a receptor results in hormonal resistance. Constitutive activation of a receptor leads to unregulated, hormone-independent activation of cellular processes.
Hormones regulate essentially every major aspect of cellular function in every organ system. Hormones control the growth of cells, ultimately determining their size and competency for cell division. Hormones regulate the differentiation of cells and their ability to survive or to undergo programmed cell death. They influence cellular metabolism, the ionic composition of body fluids, and cell membrane potential. Hormones orchestrate several complex cytoskeleton-associated events, including cell shape, migration, division, exocytosis, recycling/endocytosis, and cell-cell and cell-matrix adhesion. Hormones regulate the expression and function of cytosolic and membrane proteins, and a specific hormone may determine the level of its own receptor or the receptors for other hormones.