Endocrine System Basic Concepts PDF

Physiology Endocrine System Chapter 16 |Basic Concepts of Endocrine Regulation Endocrine System | Basic Concepts Contents : Introduction 3 Evolution Of Hormones & Their Actions On Target Cells 5 Hormone Secretion 12 Hormone Transport In The Blood 24 Hormone Action 33 Principles Of Feedback Control 4...

Physiology Endocrine System Chapter 16 |Basic Concepts of Endocrine Regulation Endocrine System | Basic Concepts Contents : Introduction 3 Evolution Of Hormones & Their Actions On Target Cells 5 Hormone Secretion 12 Hormone Transport In The Blood 24 Hormone Action 33 Principles Of Feedback Control 41 Endocrine System | Basic Concepts Introduction : In general, endocrine physiology is concerned with the maintenance of various aspects of homeostasis. The mediators of such control mechanisms are soluble factors known as hormones. The endocrine system differs from other physiological systems in that it cannot be distinctly defined based on anatomical boundaries. Endocrine System | Basic Concepts It operates as a distributed network comprising glands and circulating messengers, often under the influence of the central nervous system, the autonomic nervous system, or both. Endocrine System | Basic Concepts Evolution of Hormones & Their Actions on Target Cells : Hormones comprise steroids, amines, and peptides. Peptide hormones are by far the most numerous. Many hormones can be grouped into families reflecting their structural similarities as well as the similarities of the receptors they activate. However, the number of hormones and their diversity increases as one moves from simple to higher life forms, reflecting the added challenges in providing for homeostasis in more complex organisms. Endocrine System | Basic Concepts For example, among the peptide hormones, several are heterodimers that share a common α chain, with specificity being conferred by the β-chain. In the specific case of thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), there is evidence that the distinctive β-chains arose from a series of duplications of a common ancestral gene. Endocrine System | Basic Concepts For these and other hormones, moreover, this molecular evolution implies that hormone receptors also needed to evolve to allow for spreading of hormone actions/specificity. This was accomplished by co-evolution of the basic Gprotein–coupled receptors (GPCR) and receptor tyrosine kinases that mediate the effects of peptide and amine hormones that act at the cell surface. Endocrine System | Basic Concepts Endocrine System | Basic Concepts Steroids and thyroid hormones are distinguished by their predominantly intracellular sites of action, since they can diffuse freely through the cell membrane. They bind to a family of largely cytoplasmic proteins known as nuclear receptors. Upon ligand binding, the receptor–ligand complex translocates to the nucleus where it either homodimerizes, or associates with a distinct liganded nuclear receptor to form a heterodimer. In either case, the dimer binds to DNA to either increase or decrease gene transcription in the target tissue. Endocrine System | Basic Concepts Hormone Secretion Endocrine System | Basic Concepts Hormone Secretion : Synthesis & Processing : The regulation of hormone synthesis, of course, depends on their chemical nature. For peptide hormones as well as hormone receptors, synthesis is controlled predominantly at the level of transcription. For amine and steroid hormones, synthesis is controlled indirectly by regulating the production of key synthetic enzymes as well as by substrate availability. Endocrine System | Basic Concepts Interestingly, the majority of peptide hormones are synthesized initially as much larger polypeptide chains, and then processed intracellularly by specific proteases to yield the final hormone molecule. In some cases, multiple hormones may be derived from the same initial precursor, depending on the specific processing steps present in a given cell type. Presumably this provides for a level of genetic “economy.” It is also notable that the hormone precursors themselves are typically inactive. Endocrine System | Basic Concepts This may be a mechanism that provides for an additional measure of regulatory control, or, in the case of thyroid hormones, may dictate the site of highest hormone availability. The synthesis of all of the proteins/peptides discussed above is subject to the normal mechanisms of transcriptional control in the cell. In addition, there is provision for exquisitely specific regulation by other hormones, since the regulatory regions of many peptide hormone genes contain binding motifs for the nuclear receptors discussed above. Endocrine System | Basic Concepts For example, thyroid hormone directly suppresses TSH expression via the thyroid hormone receptor. These specific mechanisms to regulate hormone transcription are essential to the function of feedback loops, as will be addressed in greater detail below. In some cases, the abundance of selected hormones may also be regulated via effects on translation. Endocrine System | Basic Concepts For example, elevated levels of circulating glucose stimulate the translation of insulin mRNA. These effects are mediated by the ability of glucose to increase the interaction of the insulin mRNA with specific RNA binding proteins, which increase its stability and enhance its translation. The net effect is a more precise and timely regulation of insulin levels, and thus energy metabolism, than could be accomplished with transcriptional regulation alone. Endocrine System | Basic Concepts The precursors for peptide hormones are processed through the cellular machinery that handles proteins destined for export, including trafficking through specific vesicles where the propeptide form can be cleaved to the final active hormones. Mature hormones are also subjected to a variety of post translational processing steps, such as glycosylation, which can influence their ultimate biologic activity and/or stability in the circulation. Ultimately, all hormones enter either the constitutive or regulated secretory pathway. Endocrine System | Basic Concepts Secretion : The secretion of many hormones is via a process of exocytosis of stored granules. The exocytotic machinery is activated when the cell type that synthesizes and stores the hormone in question is activated by a specific signal, such as a neurotransmitter or peptide releasing factor. One should, however, contrast the secretion of stored hormones with that of those that are continually released by diffusion (eg, steroids). Endocrine System | Basic Concepts Control of the secretion of the latter molecules occurs via kinetic influences on the synthetic enzymes or carrier proteins involved in hormone production. For example, the steroidogenic acute regulatory protein (StAR) is a labile protein whose expression, activation, and deactivation are regulated by intracellular signaling cascades and their effectors, including a variety of protein kinases and phosphatases. StAR traffics cholesterol from the outer to the inner membrane leaflet of the mitochondrion. Endocrine System | Basic Concepts Regulation of steroid biosynthesis by the steroidogenic acute regulatory protein (StAR). Endocrine System | Basic Concepts Because this is a rate-limiting first step in the synthesis of the steroid precursor, pregnenolone, this arrangement permits changes in the rate of steroid synthesis, and thus secretion, in response to homeostatic cues such as trophic hormones, cytokines, and stress. An additional complexity related to hormone secretion relates to the fact that some hormones are secreted in a pulsatile manner. Secretion rates may peak and ebb relative to circadian rhythms, in response to the timing of meals, or as regulated by other pattern generators whose periodicity may range from milliseconds to years. Endocrine System | Basic Concepts Pulsatile secretion is often related to the activity of oscillators in the hypothalamus that regulate the membrane potential of neurons, in turn secreting bursts of hormone releasing factors into the hypophysial blood flow that then cause the release of pituitary and other downstream hormones in a similar pulsatile manner. There is evidence that these hormone pulses convey different information to the target tissues that they act upon compared to a steady exposure to a single concentration of the hormone. Therapeutically, pulsatile secretion may pose challenges if, due to deficiency, it proves necessary to replace a particular hormone that is normally secreted in this way. Hormone Transport In The Blood Endocrine System | Basic Concepts Hormone Transport In The Blood : In addition to the rate of secretion and its nature (steady vs. pulsatile), a number of factors influence the circulating levels of hormones. These include the rates of hormone degradation and/or uptake, receptor binding and availability of receptors, and the affinity of a given hormone for plasma carriers. Stability influences the circulating half-life of a given hormone and has therapeutic implications for hormone replacement therapy, in addition to those posed by pulsatile secretion as discussed above. Endocrine System | Basic Concepts Regulation of steroid biosynthesis by the steroidogenic acute regulatory protein (StAR). Endocrine System | Basic Concepts Plasma carriers for specific hormones have a number of important physiologic functions. First, they serve as a reservoir of inactive hormone and thus provide a hormonal reserve. Bound hormones are typically prevented from degradation or uptake. Thus, the bound hormone reservoir can allow fluctuations in hormonal levels to be smoothed over time. Plasma carriers also restrict the access of the hormone to some sites. Endocrine System | Basic Concepts Ultimately, plasma carriers may be vital in modulating levels of the free hormone in question. Typically, it is only the free hormone that is biologically active in target tissues or can mediate feedback regulation (see below) since it is the only form able to access the extravascular compartment. Catecholamine and most peptide hormones are soluble in plasma and are transported as such. In contrast, steroid hormones are hydrophobic and are mostly bound to large proteins called steroid binding proteins (SBP), which are synthesized in the liver. Endocrine System | Basic Concepts As a result, only small amounts of the free hormone are dissolved in the plasma. Specifically, sex hormone–binding globulin (SHBG) is a glycoprotein that binds to the sex hormones, testosterone and 17β-estradiol. Progesterone, cortisol, and other corticosteroids are bound by transcortin. The SBP-hormone complex and the free hormone are in equilibrium in the plasma, and only the free hormone is able to diffuse across cell membranes. Endocrine System | Basic Concepts SBP have three main functions: 1. They increase the solubility of lipid-based hormones in the blood. 2. They reduce the rate of hormone loss in the urine by preventing the hormones from being filtered in the kidney. 3. They provide a source of hormone in the bloodstream that can release free hormone as the equilibrium changes. Endocrine System | Basic Concepts It follows that an additional way to regulate the availability of hormones that bind to carrier proteins, such as steroids, is to regulate the expression and secretion of the carrier proteins themselves. This is a critical mechanism that regulates the bioavailability of thyroid hormones, for example. In a pathophysiologic setting, some medications can alter levels of binding proteins or displace hormones that are bound to them. Endocrine System | Basic Concepts In addition, some binding proteins are promiscuous and bind multiple hormones (eg, SHBG). These observations may have clinical implications for endocrine homeostasis, since free hormones are needed to feedback and control their rates of synthesis and secretion (see below). Finally, the anatomic relationship of sites of release and action of hormones may play a key role in their regulation. Endocrine System | Basic Concepts For example, a number of hormones are destroyed by passage through the pulmonary circulation or the liver. This may markedly curtail the temporal window within which a given hormone can act. Endocrine System | Basic Concepts Hormone Action : Hormones exert a wide range of distinctive actions on a huge number of target cells to effect changes in metabolism, release of other hormones and regulatory substances, changes in ion channel activity, and cell growth, among others. Ultimately, the concerted action of the hormones of the body ensures the maintenance of homeostasis. Indeed, all hormones affect homeostasis to some degree. However, a subset of the hormones, including thyroid hormone, cortisol, parathyroid hormone, vasopressin, the mineralocorticoids, and insulin, are the key contributors to homeostasis. Endocrine System | Basic Concepts TABLE: Major hormonal contributors to homeostasis Hormone Source Action Thyroid hormone Thyroid Controls basal metabolism in most tissues Cortisol Adrenal cortex Energy metabolism; permissive action for other hormones Mineralocorticoids Adrenal cortex Regulate plasma volume via effects on serum electrolytes Vasopressin Posterior pituitary Regulates plasma osmolality via effects on water excretion Parathyroid hormone Parathyroid Regulates calcium and phosphorus levels Insulin Pancreas Regulates plasma glucose concentration Endocrine System | Basic Concepts Endocrine System | Basic Concepts Hydrophilic hormones, including peptides and catecholamines, exert their acute effects by binding to cell surface receptors. Most of these are from the GPCR family. Hydrophobic hormones, on the other hand, predominantly exert their actions via nuclear receptors. There are two classes of nuclear receptors that are important in endocrine physiology. Endocrine System | Basic Concepts The first class provides direct stimulation of transcription via induction of the binding of a transcriptional co-activator when the hormonal ligand is bound. In the second class, hormone binding triggers simultaneous dislodging of a transcriptional co-repressor and recruitment of a co-activator. The latter class of receptor allows for a wider dynamic range of regulation of the genes targeted by the hormone in question. Endocrine System | Basic Concepts Endocrine System | Basic Concepts Principles Of Feedback Control Endocrine System | Basic Concepts Principles Of Feedback Control : A final general principle that is critical for endocrine physiology is that of feedback regulation. This holds that the responsiveness of target cells to hormonal action subsequently “feeds back” to control the inciting endocrine organ. Feedback can regulate the further release of the hormone in either a negative feedback or (more rarely) a positive feedback loop. Endocrine System | Basic Concepts Positive feedback relates to the enhancement or continued stimulation of the original release mechanism/stimulus. Such mechanisms are really only seen in settings that need to gather momentum to an eventual outcome, such as parturition. Negative feedback is a far more common control mechanism and involves the inhibition or dampening of the initial hormone release mechanism/stimulus. A general scheme for feedback inhibition of endocrine axes. Endocrine System | Basic Concepts Summary of feedback loops regulating endocrine axes. Endocrine System | Basic Concepts In general, the endocrine system uses a network of feedback responses to maintain a steady state. Negative feedback control systems such as those described are the most common feedback/homeostatic systems in the body. Feedback control loops also provide for diagnostic strategies in evaluating patients with suspected endocrine disorders. Endocrine System | Basic Concepts For example, in a patient being evaluated for hypothyroidism, normal levels of TSH tend to rule out a primary defect at the level of the thyroid gland itself, and rather suggest that a defect at the level of the anterior pituitary should be sought. Conversely, if TSH is elevated, it suggests that the normal ability of circulating thyroid hormone to suppress TSH synthesis has been lost, likely due to a reduction in the ability of the thyroid gland to synthesize the hormone. Chapter Summary Endocrine System | Basic Concepts Chapter Summary : The endocrine system consists of a distributed set of glands and the chemical messengers that they produce, referred to as hormones. Hormones play a critical role in ensuring homeostasis (ie, the relative stability of body systems). Hormones can be grouped into peptide/protein, amine, and steroid categories. Endocrine System | Basic Concepts Water-soluble hormones (peptides and catecholamines) bind to cell surface receptors; hydrophobic hormones diffuse into the cell and activate nuclear receptors to regulate gene transcription. The receptors and hormones appear to have evolved in parallel. Hormone availability is dictated by the rate of synthesis, the presence of releasing factors, and rates of degradation or uptake. Free hydrophobic hormones are also in equilibrium with a form bound to plasma protein carriers, the latter representing a hormone reservoir as well as an additional mechanism to regulate hormone availability. Endocrine System | Basic Concepts The synthesis and release of many hormones is subject to regulation by negative feedback loops. Disease states can arise in the setting of both hormone deficiency and excess. Hormone deficiencies may be mimicked by inherited defects in their receptors or downstream signaling pathways; hormone excess may be mimicked by autoantibodies that bind to and activate hormone receptors, or by activating mutations of these receptors.