General Chemical Structure and Function of the Endocrine System

Examples of protein/polypeptide hormones include adrenocorticotropin (ACTH) from the pituitary, insulin from the pancreas, and parathyroid hormone (PTH). These hormones range in size from three amino acids (thyrotropin-releasing hormone) to considerably larger proteins with subunit structure (eg, luteinizing hormone). They are produced in their endocrine tissue of origin by transcription/translation of the gene coding for the hormone and synthesized initially as larger products (prepro- or pre-forms) that undergo processing to authentic hormone inside the cell before secretion. Embedded in the gene coding for protein structure are amino acid sequences (signal peptides) that communicate to the cell that these molecules are destined for the regulated secretory pathway. Other post-translational modifications may occur during processing, including folding, glycosylation, disulfide bond formation, and subunit assembly. The folded and processed hormone is then stored in secretory granules or vesicles in preparation for release by the exocytotic process. Release of hormone is triggered by unique signals; eg, secretion of PTH is stimulated by a decline in the concentration of ionic or free calcium present in the extracellular fluid bathing the parathyroid chief cells. In most cases, cells producing protein/polypeptide hormones store significant amounts of these substances intracellularly; therefore, they can respond quickly when increased amounts are needed in circulation. Generally, protein/polypeptide hormones have relatively short half-lives in blood (minutes) and do not travel in blood-bound carrier proteins (exceptions exist, eg, insulin-like growth factor 1 is highly protein bound).

Protein/polypeptide hormones act on their target cells by binding to receptors located on the cell surface. These receptors are proteins and glycoproteins embedded in the cell membrane that traverse the membrane at least once so that the receptor is exposed to both the extracellular and intracellular environments. There are several classes or types of cell surface hormone receptors that translate the hormonal message to the cell interior by different means. Some are the G-protein (guanosine) coupled type, with seven transmembrane spanning domains. After hormone binding, these receptors activate a G-protein that is also located in the membrane. One or more of the G-protein subunits affects other downstream molecules (known as effectors) such as enzymes (eg, adenylate cyclase or phospholipase C) or ion channels. Activation may result in production of a second messenger, such as cyclic AMP, that can then bind to protein kinase A, causing its activation and subsequent phosphorylation of other proteins. Thus, signal transduction is a cascading and often amplifying series of events triggered when a hormone binds to its receptor. The ultimate effects in target cells are multiple and include such things as triggering secretion, increasing uptake of a molecule, or activating mitosis. Other receptors, such as the one for insulin, not only bind hormone but also act as enzymes, with the ability to phosphorylate tyrosine residues. The phosphorylated tyrosines in turn serve as docking sites for downstream signaing proteins.

Cell surface receptors are dynamic; their numbers and/or activity change with physiologic conditions. In some cases, such as exposure to excessive amounts of hormone, receptor down-regulation can occur. Down-regulation and a decline in target tissue responsiveness may be due to internalization of receptors after ligand binding or to desensitization whereby the receptor is chemically modified and becomes less active. Conversely, a lack of hormonal exposure can lead to an increase in receptor numbers on target cells (up-regulation). Diseases have been linked to mutations in hormone receptors, which can result in inactivation or constitutive or nonhormonal activation of the pathway. In some instances, a single amino acid substitution is responsible.

Steroid hormones are derivatives of cholesterol and include products of the adrenal cortex, ovaries, and testes as well as the related molecule, vitamin D. Unlike protein/polypeptide hormones, steroid hormones are not stored in large amounts. When needed, they are rapidly synthesized from cholesterol by a series of enzymatic reactions. Most of the cholesterol needed for rapid steroid hormone synthesis is stored intracellularly in the tissue of origin. In response to appropriate signals, the precursor is moved to organelles (mitochondria and smooth endoplasmic reticulum), where a series of enzymes (eg, isomerases, dehydrogenases) rapidly convert the molecule to the appropriate steroid hormone. The identity of the final steroidal product is thus dictated by the set of enzymes expressed in that tissue.

Steroid hormones are hydrophobic and pass through cell membranes easily. In the blood, they are bound to a great extent to carrier proteins. Albumin binds many steroids fairly loosely; in addition, specific binding globulins exist for many steroid hormones. Most of the steroid hormone in circulation is bound to carrier proteins, and a small fraction circulates free or unbound. This latter fraction is thought to be available for target cell entry, ie, the biologically active portion. A rapid equilibrium exists between protein-bound and unbound steroid in extracellular fluid. Possible roles for steroid hormone–binding proteins include aiding in tissue delivery of steroids by providing an even distribution to all cells within a target tissue, buffering against large fluctuations in free hormone, and prolonging the half-life of steroids in blood. Relative to protein/polypeptide hormones, steroids usually have longer half-lives, often in the range of many minutes to hours.

Steroid hormones act on target cells via receptors located in the cell interior. These receptors are generally found in the nucleus, although some appear to reside, when unoccupied, in the cytoplasm. There are several classes of steroid receptors—those for glucocorticoids, mineralocorticoids, progestins, etc. Steroid receptors comprise a family of related proteins that also show homology to receptors for the thyroid hormones and vitamin D. The receptor has regions or domains that carry out specific tasks: one for recognition and binding of the steroid, another for binding to a specific region on chromosomal DNA, and a third for helping regulate the transcriptional complex. Steroid hormones enter targets by diffusing through the cell membrane and then binding to the receptor, causing a conformational change in the new complex. This, in turn, leads to release of associated proteins (eg, heat-shock proteins) and movement to the nucleus (if necessary), followed by binding of the complex to regions of DNA located near specific steroid-regulated genes. The result is a change in the rate of transcription of specific genes, either increasing or decreasing their expression. Thus, steroid hormones primarily function by affecting the production rates of specific messenger RNA and proteins in targets. Steroid action is relatively slow in onset (hours) but may be long lasting because of the duration of production and half-lives of the messenger RNA and proteins induced in target cells. It is increasingly clear that some steroids also act via nongenomic mechanisms. For example, many of the anti-inflammatory effects of glucocorticoids are thought to be due to the glucocorticoid-receptor complex binding to, and inhibiting the action of, pro-inflammatory transcription factors inside cells.

Steroids in the blood are eliminated by metabolism in the liver. Reduced forms are produced and subsequently conjugated to glucuronic acid and sulfate. These metabolites are freely soluble in blood and are eliminated from the body by renal excretion and through the GI tract. Small amounts of free steroid hormone are also directly excreted by the kidneys.

This class of hormones is made by chemical modification of amino acids, mainly tyrosine. They include thyroid hormones and the catecholamines epinephrine and norepinephrine. Thyroxine (T₄) and triiodothyronine (T₃) are stored in the thyroid as a part of thyroglobulin; secretion of these hormones involves thyroidal cell uptake and breakdown of this large molecule liberating T₄ and T₃. Thyroid hormones act on targets much like steroids; they are relatively water insoluble, transported by carrier proteins in blood, and act on targets via intracellular receptors. Catecholamines are manufactured by hydroxylation, decarboxylation, and methylation of tyrosine and are secreted into the blood from the adrenal medulla. They have exceedingly short half-lives (<5 min), are not protein bound, and act on targets via cell surface receptors (α- and β-adrenergic receptors).