Chapter summary

It is impossible to overstate the importance of the endocrine system in regulation of homeostasis, tissue and organ development, and physiological processes in general. The nervous system and endocrine system regulate virtually all physiological functions.

Cell signaling

Broadly speaking, hormones influence target cells (those that express receptors capable of binding the hormone) can be divided into those that initially act at the surface of the target cells versus those that act internally. Surface-acting hormones are typically peptides that are too large to pass across the plasma membrane of the target cell. These hormones are often described as having a second messenger mech­anism of action. This simply means that the hormone first binds to a membrane receptor, which induces a biochemical change inside the cell that is responsible for the actions attributed to the hormone. Dr. Earl Sutherland (1971 Nobel Prize) was the first to describe the second messenger pathway. He found that for epinephrine to induce liver cells to convert glycogen to glucose, the cells had to trigger an increase in intracellular cyclic AMP. Drs. Martin Rodbell and Alfred Gilman worked out the biochemical steps in detail and were awarded the 1994 Nobel Prize. Surface receptors can be grouped in four classes: seven-transmembrane domain, single-transmem­brane, cytokine superfamily, and guanyl cyclase

receptors. In some cases, the receptors when acti­vated (bound by the hormone) become directly enzy­matically active (often acting as kinases in which phosphorylation of a cellular protein initiates a cascade of reactions), which is responsible for the hormone effect.

For hormones that can enter cells, receptors are typically located in the cell nucleus. In essence many of these hormones, when bound to their receptors, are acting as transcription factors that increase gene activation and subsequently production of mRNA and production of proteins responsible for the observed hormone effects. Generally speaking, such hormones are usually associated with longer or more slowly initiated hormone effects, but there are exceptions.

How effective a given hormone can be is also directly related to the number of receptors available and the concentration of the hormone in the blood or interstitial fluids. Intuitively, all things being equal an increase in the concentration of the hormone cor­respondingly increases the likelihood that more of the available receptors will be bound and thus it is more likely that a hormone-induced response will occur. This relationship is known as the law of mass action. It is well recognized that there can be dra­matic and rapid changes in the concentration of hor­mones in the blood. For example, after a carbohydrate meal or a glucose challenge, insulin rapidly increases. Other hormones (growth hormone, prolactin, corti­sol, etc.) are secreted in acute episodes and/or daily and seasonal rhythms. One of the great break advances in endocrinology occurred in the 1970s when RIAs were developed that were capable of accurately measuring concentrations of many hor­mones in the blood, milk, saliva and other biological fluids. Prior to this time endocrinologists often relied on cumbersome, much less sensitive bioassays. The RIA depends on the binding of the hormone in ques­tion to specific antibodies and the capacity of stan­dards or hormones in unknown samples to compete for these binding sites.

Major hormones

With the advent of molecular and cellular tools, the list of hormones and growth factors seems to expand daily.

The somatomedin hypothesis arose from observa­tions that many of the effects associated with GH seem to be indirect.

The fundamental nature of the endocrine pancreas seems to be driven home daily in face of the obesity epidemic in the developed world and increasing prevalence of type II (adult onset diabetes). The pan­creatic islets with alpha, beta, and delta cells synthe­size and secrete glucagon, insulin, and somatomedin, respectively. Simplistically, diabetes is essentially elevated circulating concentrations of blood glu­cose that results from either a failure of insulin to be secreted (as normal) in response to increased blood glucose or a failure of insulin to induce the appropriate response (insulin receptor signaling issue,

autoantibodies against insulin, its receptor or beta cells). The classic tests for diabetes include measure­ment of glucose in urine (usually there should none) and/or the glucose challenge. In this test subjects are either infused (I.V.) with glucose or given an oral bolus of glucose. In normal subjects the peak in blood glucose is blunted and relatively short-lived. With diabetes, the peak concentration is usually higher and the period of elevation longer. The physiological consequences of prolonged elevations in blood glucose can be devastating: vision, circulatory, and metabolic problems (Ingvartsen and Andersen, 2000).

Like the pancreas, the adrenal gland and its hor­mones are equally critical. The adrenal has two primary regions: cortex and medulla. The medulla essentially functions like postganglionic tissue of the autonomic nervous system, except it secretes epi­nephrine into the bloodsteam rather than the closely related neurotransmitter norepinephrine. Both the cortex and medulla are key players in the fight-or- flight responses associated with high-stress situa­tions. The adrenal cortex has three distinct zones: glomerulosa, fasciculata, and reticularis. It produced multiple steroid hormones but the two primary ones are aldosterone and corticosteroids (cortisol, corti­costerone, etc., depending on the species).

The thyroid and its hormones T₃ and T₄ are closely tied to metabolic rate, tissue development, and general health. T₃ is much more biologically potent than T₄, and it is now known that several tissues (mammary gland, liver, kidney) have the capacity to deiodinate T₄ to produce T₃ locally in the tissue. Either hyper or hyposecretion of thyroid hormones can have dramatic metabolic effects in mature animals, and in young animals hyposecretion can markedly retard neural development. The thyroid hormones are secreted by the follicular cells of the thyroid in the Iumenal spaces similar to the mammary alveoli as a part of a larger protein thyroglobulin. When signaled to secrete, the colloid is reabsorbed, the protein is cleaved, and the thyroid hormones are released into circulation. The hormone CT is pro­duced by parafollicular or C cells located in the inter­stitial regions between the thyroid follicles. It acts in calcium homeostasis by inhibiting bone reabsorption and thus blunts increase in calcium.

The parathyroid glands occur in pairs in each half of the thyroid gland. They are responsible for the secretion of PTH. The primary effect of PTH is to increase blood calcium (bone reabsorption, increase gut uptake).

The list of important and potent growth factors is staggering and growing, but some of the better rec­ognized include atrial natriuretic peptide, EGF, fibro­blast growth factor, ghrelin, interleukins, leptin, and transforming growth factors. Moreover, many of the growth factors have many individual members within each class.

The interface between the nervous system and endocrine system to regulate homeostasis and physi­ological development (reproduction, lactation, growth) becomes ever more intertwined and convoluted with each passing year.

Review questions and answers are available online.

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