General Chemical Structure and Function of the Endocrine System of Animals
The endocrine system consists of ductless vascular tissues that release a variety of hormones in regulated fashion. Endocrine hormones control or regulate a multitude of biological processes in virtually all tissues. Endocrine dysfunction is common in species of veterinary importance, and a knowledge of hormonal chemistry and mechanisms of action is central to understanding the diagnosis and treatment of endocrine diseases.
There are three main chemical categories of hormones: protein and polypeptide hormones, steroid hormones, and modified amino acid hormones, as outlined in the table Major Chemical Classes of Hormones Overview of Major Chemical Classes of Hormones .
Protein and Polypeptide Hormones in Animals
Examples of protein and polypeptide hormones include ACTH from the pituitary, insulin from the pancreas, and parathyroid hormone (PTH) from the parathyroid glands. These hormones range in size from three amino acids (thyrotropin-releasing hormone) to considerably larger proteins with subunit structure (eg, luteinizing hormone).
Protein and polypeptide hormones are produced in their endocrine tissue of origin by transcription of the gene coding for the hormone and subsequent translation. Protein and polypeptide hormones are synthesized initially as larger products (preprohormone or prehormone forms) that are processed to authentic hormone inside the cell before secretion. Embedded in the gene that codes 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 posttranslational 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 exocytosis.
Release of hormone is triggered by signals unique to that hormone. For example, secretion of PTH is stimulated by a decline in the concentration of ionic or free calcium present in the extracellular fluid that bathes the parathyroid chief cells. Insulin, by contrast, is secreted in response to rising glucose concentrations that bathe the pancreatic beta cells.
Most cells that produce protein and polypeptide hormones store substantial amounts of these substances intracellularly. This allows a quick response when increased amounts are needed in circulation. Generally, protein and polypeptide hormones have relatively short half-lives in the blood (minutes), and they do not travel in blood-bound carrier proteins (exceptions exist; eg, insulin-like growth factor 1 is highly protein bound).
Protein and 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 extend across the membrane at least once, such that the receptor is exposed to both the extracellular and intracellular environments.
Several classes or types of cell-surface hormone receptors translate hormonal messages to the cell interior by different means.
In one class, the receptors are coupled to G (guanosine) proteins. G protein–coupled receptors (GPCRs) have seven membrane-spanning domains (and are also known as 7-transmembrane receptors). After binding hormone, these receptors activate a G protein that is also located in the membrane. One or more of the G-protein subunits affects (activates or inhibits) other downstream molecules (known as effectors) such as enzymes (eg, adenylate cyclase or phospholipase C) or ion channels.
Activation of a G protein may result in the production of a second messenger, such as cyclic adenosine monophosphate (cyclic AMP or cAMP), that can then bind to protein kinase A, causing its activation and the 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 initial target cell effects that follow binding of a protein or polypeptide hormone occur very quickly (seconds to minutes). Ultimately, the hormones affect target cells in multiple ways, including triggering secretion, increasing the 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 tyrosine residues, in turn, serve as docking sites for downstream signaling proteins.
Cell-surface receptors are dynamic; their numbers and activity change with different physiologic conditions.
In some cases, such as exposure to excessive amounts of hormone, receptors can be downregulated. Downregulation 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, lack of exposure to hormones can lead to an increase in receptor numbers on target cells (ie, upregulation).
Diseases have been linked to mutations in hormone receptors, which can result in inactivation or constitutive or nonhormonal activation of the pathway. Sometimes a single amino acid substitution is the cause.
Steroid Hormones in Animals
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 and polypeptide hormones, mature 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 converts 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 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 steroid hormones in circulation are bound to carrier proteins; a small fraction circulate freely or unbound. Freely circulating steroids are thought to be the biologically active portion of steroid hormones—ie, available to enter target cells. A rapid equilibrium exists between protein-bound and unbound steroids in extracellular fluid.
Possible roles for proteins that bind steroid hormones 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 hormones, and prolonging the half-life of steroids in blood.
Relative to protein and 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—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.
Steroid hormone receptors have 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 to 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 function primarily by affecting the production rates of specific messenger RNA and proteins in targets.
Steroid action is relatively slow in onset (hours) but may last a long time because of the duration of production and half-lives of the messenger RNA and proteins induced in target cells.
Some steroids also act via nongenomic mechanisms. For example, many of the anti-inflammatory effects of glucocorticoids are thought to come about because the glucocorticoid-receptor complex binds to and inhibits the action of proinflammatory transcription factors inside cells. In addition, rapid effects of steroids are likely mediated, at least in part, by their binding to nonclassical receptors located on target cell membranes.
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 hormones are also directly excreted by the kidneys.
Modified Amino Acid Hormones in Animals
Hormones in this class are made by the 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 the large molecule thyroglobulin; secretion of these hormones involves thyroidal cell uptake and breakdown of this large molecule, liberating T4 and T3.
Iodine plays a central and essential role in thyroid hormone synthesis.
Thyroid hormones act on targets in much the same way that steroids do: they are relatively water insoluble, transported by carrier proteins in blood, and act on targets via intracellular receptors. Thyroid hormones are transported into target cells via cell membrane transporters such as monocarboxylate transporter 8 and organic anion transporting polypeptide.
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 minutes), are not protein bound, and act on targets via cell-surface receptors (alpha- and beta-adrenergic receptors).