Principles of Endocrinology
Introduction
Roughly a hundred years ago, Starling coined the term hormone to describe secretin, a substance secreted by the small intestine into the blood stream to stimulate pancreatic secretion. In his Croonian Lectures, Starling considered the endocrine and nervous systems as two distinct mechanisms for coordination and control of organ function. Thus, endocrinology found its first home in the discipline of mammalian physiology. And start this condition the people want to answer what is the principle of endocrinology.
Work over the next several decades by biochemists, physiologists, and clinical investigators led to the characterization of many hormones secreted into the blood stream from discrete glands or other organs. These investigators showed for the first time that diseases such as hypothyroidism and diabetes could be treated successfully by replacing specific hormones. These initial triumphs formed the foundation of the clinical specialty of endocrinology.
Advances in cell biology, molecular biology, and genetics over the ensuing years began to help explain the mechanisms of endocrine diseases and of hormone secretion and action. Although these advances have embedded endocrinology into the framework of molecular cell biology, they have not changed the essential subject of endocrinologythe signaling that coordinates and controls the functions of multiple organs and processes. Here we would like to survey the general themes and principles that underpin the diverse approaches used by clinicians, physiologists, biochemists, cell biologists, and geneticists to understand the endocrine system.
THE EVOLUTIONARY PERSPECTIVE
Hormones can be defined as chemical signals secreted into the blood stream that act on distant tissues, usually in a regulatory fashion. Hormonal signaling represents a special case of the more general process of signaling between cells. Even unicellular organisms such as baker’s yeast, Saccharomyces cerevisiae, secrete short peptide mating factors that act on receptors of other yeast cells to trigger mating between the two cells. These receptors resemble the ubiquitous family of mammalian 7-transmembrane spanning receptors that respond to ligands as diverse as photons and glycoprotein hormones. Because these yeast receptors trigger activation of heterotrimeric G proteins just as mammalian receptors do, this conserved signaling pathway must have been present in the common ancestor of yeast and humans.
Signals from one cell to adjacent cells, so-called paracrine signals, often trigger cellular responses that use the same molecular pathways used by hormonal signals. For example, the sevenless receptor controls the differentiation of retinal cells in the Drosophila eye by responding to a membrane-anchored signal from an adjacent cell. Sevenless is a membrane-spanning receptor with an intracellular tyrosine kinase domain that signals in a way that closely resembles the signaling by hormone receptors such as the insulin receptor tyrosine kinase. Since paracrine factors and hormones can share signaling mechanisms it is not surprising that hormones can, in some settings, act as paracrine factors. Testosterone, for example, is secreted into the blood stream but also acts locally in the testes to control spermatogenesis. Insulin-like growth factor I (IGF-I) is a hormone secreted into the blood stream from the liver and other tissues, but it is also a paracrine factor made locally in most tissues to control cell proliferation. Further, one receptor can mediate the actions of a hormone, such as parathyroid hormone, and of a paracrine factor, such as parathyroid hormonerelated protein.
Target cells respond similarly to signals that reach them from the blood stream (hormones) or from the cell next door (paracrine factors); the cellular response machinery does not distinguish the sites of origin of signals. The shared final common pathways used by hormonal and paracrine signals should not, however, obscure important differences between hormonal and paracrine signaling system . Paracrine signals do not travel very far; consequently, the specific site of origin of a paracrine factor determines where it will act and provides specificity to that action. When the paracrine factor BMP4 is secreted by cells in the developing kidney, it regulates the differentiation of renal cells; when BMP4 is secreted by cells in bone, it regulates bone formation. Thus, the site of origin of BMP4 determines its physiologic role. In contrast, since hormones are secreted into the blood stream, their sites of origin are often divorced from their functions. We know nothing about thyroid hormone function, for example, that requires that the thyroid gland to be in the neck.
Because the specificity of action of paracrine factors is so dependent on their precise site of origin, elaborate mechanisms have evolved to regulate and constrain the diffusion of paracrine factors. Paracrine factors of the hedgehog family, for example, are covalently bound to cholesterol to constrain the diffusion of these molecules in the extracellular milieu. Most paracrine factors interact with binding proteins that block their action and control their diffusion. Chordin, noggin, and many other distinct proteins all bind to various members of the BMP family to regulate their action, for example. Proteases such as tolloid then destroy the binding proteins at specific sites to liberate BMPs so that the BMPs can act on appropriate target cells.
Hormones have rather different constraints. Because they diffuse throughout the body, they must be synthesized in enormous amounts relative to the amounts of paracrine factors needed at specific locations. This synthesis usually occurs in specialized cells designed for that specific purpose. Hormones must then be able to travel in the blood stream and diffuse in effective concentrations into tissues. Therefore, for example, lipophilic hormones bind to soluble proteins that allow them to travel in the aqueous media of blood at relatively high concentrations. The ability of hormones to diffuse through the extracellular space means that the local concentration of hormone at target sites will rapidly decrease when glandular secretion of the hormone stops. Because hormones diffuse throughout extracellular fluid quickly, hormonal metabolism can occur in specialized organs such as the liver and kidney in a way that determines the effective concentration of the hormones in other tissues.
Paracrine factors and hormones thus use several distinct strategies to control their biosynthesis, sites of action, transport, and metabolism. These differing strategies may partly explain why a hormone such as IGF-I, unlike its close relative insulin, has multiple binding proteins that control its action in tissues. As noted earlier, IGF-I has a double life as both a hormone and a paracrine factor. Presumably, the local actions of IGF-I mandate an elaborate binding protein apparatus.
All the major hormonal signaling programsG proteincoupled receptors, tyrosine kinase receptors, serine/threonine kinase receptors, ion channels, cytokine receptors, nuclear receptorsare also used by paracrine factors. In contrast, several paracrine signaling programs are used only by paracrine factors and are probably not used by hormones. For example, Notch receptors respond to membrane-based ligands to control cell fate, but no bloodborne ligands use Notch-type signaling (at least none is currently known). Perhaps the intracellular strategy used by Notch, which involves cleavage of the receptor and subsequent nuclear actions of the receptor’s cytoplasmic portion, is too inflexible to serve the purposes of hormones.
The analyses of the complete genomes of multiple bacterial species, the yeast Saccharomyces cerevisiae, the fruit fly Drosophila melanogaster, the worm Caenorhabitis elegans, the plant Aradopsis thaliana, and humans have allowed a comprehensive view of the signaling machinery used by various forms of life. As noted already, S. cerevisiae uses G proteinlinked receptors; this organism, however, lacks tyrosine kinase receptors and nuclear receptors that resemble the estrogen/thyroid receptor family. In contrast, the worm and fly share with humans the use of each of these signaling pathways, although with substantial variation in numbers of genes committed to each pathway. For example, the Drosophila genome encodes 20 nuclear receptors, the C. elegans genome encodes 270, and the human genome encodes (tentatively) more than 50. These patterns suggest that ancient multicellular animals must have already established the signaling systems that are the foundation of the endocrine system as we know it in mammals.
Even before the sequencing of the human genome, sequence analyses had made clear that many receptor genes are found in mammalian genomes for which no clear ligand or function was known. The analyses of these “orphan” receptors has succeeded in broadening the current understanding of hormonal signaling. For example, the liver X receptor (LXR) was one such orphan receptor found when searching for unknown nuclear receptors. Subsequent experiments showed that oxygenated derivatives of cholesterol are the ligands for LXR, which regulates genes involved in cholesterol and fatty acid metabolism.[1] The example of LXR and many others raise the question of what constitutes a hormone. The classical view of hormones is that they are synthesized in discrete glands and have no function other than activating receptors on cell membranes or in the nucleus. In contrast, cholesterol, which is converted in cells to oxygenated derivatives that activate the LXR, uses a hormonal strategy to regulate its own metabolism. Other orphan nuclear receptors respond similarly to ligands, such as bile acids and fatty acids. These “hormones” have important metabolic roles quite separate from their signaling properties, although the hormone-like signaling serves to allow regulation of the metabolic function. The calcium-sensing receptor is an example from the G proteinlinked receptor family of receptors that responds to a nonclassical ligand, ionic calcium. Calcium is released into the blood stream from bone, kidney, and intestine and acts on the calcium-sensing receptor in parathyroid cells, renal tubular cells, and other cells to coordinate cellular responses to calcium. Thus, many important metabolic factors have taken on hormonal properties as part of a regulatory strategy.
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