After studying this chapter, you should be able to:
Describe hormones and their contribution to whole body homeostatic mechanisms.
Understand the chemical nature of different classes of hormones and how this determines their mechanism of action on target cells.
Define how hormones are synthesized and secreted by cells of endocrine glands, including how peptide hormones are cleaved from longer precursors.
Explain the relevance of protein carriers in the blood for hydrophobic hormones, and the mechanisms that determine the level of free circulating hormones.
Understand the principles of feedback control for hormone release and its relevance for homeostasis.
Understand the principles governing disease states that result from over- or under-production of key hormones.
This section of the text deals with the various endocrine glands that control the function of multiple organ systems of the body. 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 word hormone was derived from the Greek horman, meaning to set in motion. In preparation for specific discussions of the various endocrine systems and their hormones, this chapter will address some concepts of endocrine regulation that are common among all systems.
Another feature of endocrine physiology to keep in mind is that, unlike other physiological systems that are considered in this text, the endocrine system cannot be cleanly defined along anatomic lines. Rather, the endocrine system is a distributed system of glands and circulating messengers that is often stimulated by the central nervous system and/or autonomic nervous system.
EVOLUTION OF HORMONES AND THEIR ACTIONS ON TARGET CELLS
As noted in the introduction to this section, 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. 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. 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 G-protein coupled receptors (GPCR) and receptor tyrosine kinases that mediate the effects of peptide and amine hormones that act at the cell surface (see Chapter 2). The underlying ancestral relationships sometimes re-emerge, however, in the cross-reactivity that may be seen when hormones rise to unusually high levels (eg, endocrine tumors).
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. Individual members of the nuclear receptor family have a considerable degree of homology, perhaps implying a common ancestral gene, and share many functional domains, such as the zinc fingers that permit DNA binding. However, sequence variations allow for ligand specificity as well as binding to specific DNA motifs. In this way, the transcription of distinct genes is regulated by individual hormones.
SYNTHESIS AND 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.
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. 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 (see Chapter 2). 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. 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. 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.
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 posttranslational processing steps, such as glycosylation, which can influence their ultimate biological activity and/or stability in the circulation. Ultimately, all hormones enter either the constitutive or regulated secretory pathway (see Chapter 2).
The secretion of many hormones is via a process of exocytosis of stored granules, as discussed in Chapter 2. 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). 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. 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 (Figure 16–1).
FIGURE 16–1 Regulation of steroid biosynthesis by the steroidogenic acute regulatory protein (StAR). Extracellular signals activate intracellular kinases that, in turn, phosphorylate transcription factors that upregulate StAR expression. StAR is activated by phosphorylation, and facilitates transfer of cholesterol from the outer to inner mitochondrial membrane leaflet. This then allows entry of cholesterol into the steroid biosynthetic pathway, beginning with pregnenolone.
An additional complexity related to hormone secretion relates to the fact that some hormones are secreted in a pulsatile fashion. 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. 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 fashion (see Chapters 17 and 18). There is evidence that these hormone pulses convey different information to the target tissues that they act upon than 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
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 (Figure 16–2). 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.
FIGURE 16–2 Summary of factors that determine the level of free hormones circulating in the bloodstream. Factors that increase (green upward arrow) or decrease (red downward arrow) hormone levels are shown. Free hormones also equilibrate with the forms bound to either receptors or plasma carrier proteins.
Plasma carriers for specific hormones have a number of important physiological 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. 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. 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. SBP have three main functions: they increase the solubility of lipid based hormones in the blood, they reduce the rate of hormone loss in the urine by preventing the hormones from being filtered in the kidney, and as mentioned above, they provide a source of hormone in the bloodstream that can release free hormone as the equilibrium changes. 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 (see Chapter 19).
In a pathophysiological setting, some medications can alter levels of binding proteins or displace hormones that are bound to them. 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. 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.
As we will see in later chapters, 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 (Clinical Box 16–1). 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, as detailed in Table 16–1, are the key contributors to homeostasis. These include thyroid hormone, cortisol, parathyroid hormone, vasopressin, the mineralocorticoids, and insulin. Detailed information on the precise biological effects of these molecules can be found in subsequent chapters.
CLINICAL BOX 16–1
Breast cancer is the most common malignancy of women, with about 1 million new cases diagnosed each year worldwide. The proliferation of more than two-thirds of breast tumors are driven by the ovarian hormone, estrogen, by virtue of the fact that the tumor cells express high levels of posttranslationally modified estrogen receptors (ER). The clinical significance of these molecular findings has been known for more than 100 years, since the Scottish surgeon, Sir Thomas Beatson, reported delayed disease progression in patients with advanced breast cancer following removal of their ovaries. In modern times, determination of whether a given breast cancer is, or is not, ER-positive is a critical diagnostic test that guides treatment decisions, as well as an important prognosticator. ER-positive tumors are typically of lower grade, and patients with such tumors have improved survival (although the latter is likely due, at least in part, to the availability of excellent treatment options for ER-positive tumors compared with those that are ER-negative—see below).
Estrogen-responsive breast tumors are dependent on the presence of the hormone for growth. In modern times, cells can be deprived of the effects of estrogen pharmacologically, rather than resorting to oophorectomy. Tamoxifen and related agents specifically inhibit the receptor and may also hasten its degradation. In postmenopausal women, where estrogen is derived from the metabolism of testosterone in extragonadal tissues rather than from the ovaries, aromatase inhibitors inhibit the conversion of androgens to estrogen, and thereby deprive tumor cells of their critical signal for continued proliferation.
TABLE 16–1 Major hormonal contributors to homeostasis.
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, in the other hand, predominantly exert their actions via nuclear receptors. There are two classes of nuclear receptors that are important in endocrine physiology. The first of these provide for 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.
In recent years, it has become apparent that a number of receptors for steroid and other hydrophobic hormones are extranuclear, and some may even be present on the cell surface. The characterization of such receptors at a molecular level, their associated signaling pathways, and indeed proof of their existence has been complicated by the ability of hydrophobic hormones to diffuse relatively freely into all cellular compartments. These extranuclear receptors, some of which may be structurally related or even identical to the more classical nuclear receptors, are proposed to mediate rapid responses to steroids and other hormones that do not require alterations in gene transcription. The physiological effects at these receptors may therefore be distinct from those classically associated with a given hormone. Evidence is accumulating, for example, that plasma membrane receptors for estrogen can mediate acute arterial vasodilation as well as reducing cardiac hypertrophy in pathophysiological settings. Functions such as these may account for differences in the prevalence of cardiovascular disease in pre and postmenopausal women. In any event, this active area of biomedical investigation is likely to broaden our horizons of the full spectrum of action of steroid hormones.
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. 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 is depicted in Figure 16–3.
FIGURE 16–3 Summary of feedback loops regulating endocrine axes. CNS, central nervous system. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010.)
In general, the endocrine system uses a network of feedback responses to maintain a steady state. Steady state can be explained using blood osmolality as an example (Figure 16–4). Blood osmolality in humans must be maintained within a physiological range of 275–299 mOsm, and to maintain homeostasis this variable should not exceed that range. To ensure that osmolality does not change in the context of an open system, processes are in place that will add or remove water from the system to ensure a constant osmolality. The osmolality of blood will increase with dehydration and decrease with overhydration. If blood osmolality increases outside the ideal range (by 10 mOsm or more), osmoreceptors are activated. These signal release of the peptide hormone, vasopressin, into the circulation (from the pituitary). Vasopressin acts on the renal collecting duct, and increases the permeability of the plasma membrane to water via the insertion of a protein called an aquaporin. Water is then moved from the urine into the circulation via transcellular transport. The reabsorption of water from the urine to the blood resets the osmolality of the blood to within the physiological range. The decrease in blood osmolality then exerts a negative feedback on the cells of the hypothalamus and the pituitary and vasopressin release is inhibited, meaning that water reabsorption from the urine is reduced. Further details of this collaboration between the kidneys, hypothalamus and pituitary are found in Chapter 38.
FIGURE 16–4 Feedback loop that ensures homeostasis of blood osmolality. An increase in blood osmolality triggers the thirst mechanism as well as renal conservation of water via the release of vasopressin from the hypothalamus. Both outcomes decrease blood osmolality back towards the normal range, which feeds back to terminate hypothalamic signaling.
Negative feedback control systems such as those described are the most common feedback/homeostatic systems in the body. Other examples include temperature regulation (see Chapter 17) and the regulation of blood glucose concentrations (see Chapter 24). Feedback control loops also provide for diagnostic strategies in evaluating patients with suspected endocrine disorders. For example, in a patient being evaluated for hypothyroidism, normal levels of TSH (see Chapter 19) 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 (Clinical Box 16–2).
CLINICAL BOX 16–2
Approach to the Patient with Suspected Endocrine Disease
Unlike many of the disorders of individual organ systems considered elsewhere in this volume, the symptoms of endocrine disease may be protean because of the number of body systems that are impacted by hormonal action. Further, many endocrine glands are relatively inaccessible to direct physical examination. Endocrine disorders must therefore be diagnosed on the basis of the symptoms they produce in concert with appropriate biochemical testing. Radioimmunoassays for specific hormones remain the mainstay of diagnostic endocrinolology and can be used to establish steady state concentrations as well as dynamic changes of the hormone in question (the latter requiring repeated blood sampling over time). In addition, the principles of feedback regulation of hormone synthesis and release may allow the physician to pinpoint the likely locus of any defect by comparing the levels of hormones in the same axis. For example, if testosterone levels are low but those of luteinizing hormone (LH) are high, this suggests that the testes are unable to respond to LH. Conversely, if both testosterone and LH are low, the problem is more likely to be at the level of the pituitary. Synthetic hormones can also be administered exogenously to test whether increased basal levels of a given hormone can be suppressed, or abnormally low levels can be stimulated by a relevant upstream agent. An example of applying this type of reasoning to the evaluation of suspected hypothyroidism is provided in Figure 16–5.
The appropriate treatment of endocrine disorders depends on their underlying basis. For example, if a particular hormone or its releasing factor is deficient, hormone replacement therapy is often indicated to ameliorate symptoms as well as long-term negative outcomes (Figure 16–5).
FIGURE 16–5 Summary of a strategy for the laboratory evaluation of hypothyroidism. TSH, thyroid stimulating hormone; T4, thyroid hormone; TPOAb+, positive for autoantibodies to thyroid peroxidase; TPOAb–, antiperoxidase antibodies not present. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010.)
TYPES OF ENDOCRINE DISORDERS
It is pertinent also to discuss briefly the types of disease states where endocrine physiology can become deranged. Additional details of these disease states can be found in ensuing chapters.
Deficiencies of particular hormones are most commonly seen in the setting where there is destruction of the glandular structure responsible for their production, often as a result of inappropriate autoimmune attack. For example, in type 1 diabetes mellitus, pancreatic β cells are destroyed leading to an inability to synthesize insulin, often from a very young age. Similarly, hormonal deficiencies arise when there are inherited mutations in the factors responsible for their release or in the receptors for these releasing factors. Defects in the enzymatic machinery needed for hormone production, or a lack of appropriate precursors (eg, iodine deficiency leads to hypothyroidism) will also reduce the amount of the relevant hormone available for bodily requirements.
Many of the consequences of hormone deficiency can by reproduced in disease states where adequate levels of a given hormone are synthesized and released, but the target tissues become resistant to the hormone’s effects. Indeed, there is often overproduction of the implicated hormone in these conditions because the feedback loops that normally serve to shut off hormone synthesis and/or secretion are similarly desensitized. Mutations in hormone receptors (especially nuclear receptors) may result in heritable syndromes of hormone resistance. These syndromes, while relatively rare, usually exhibit severe outcomes, and have provided insights into the basic cell biology of hormone signaling. Functional hormone resistance that develops over time is also seen. Resistance arises from a relative failure of receptor signaling to couple efficiently to downstream intracellular effector pathways that normally mediate the effects of the hormone. The most common example of this is seen in type 2 diabetes mellitus. Target tissues for insulin gradually become more and more resistant to its actions, secondary to reduced activation of phosphatidylinositol 3-kinase and other intracellular signaling pathways. A key factor precipitating this outcome is obesity. In addition, because of excessive insulin secretion, pancreatic β cells become “exhausted” and may eventually fail, necessitating treatment with exogenous insulin. An important therapeutic goal, therefore, is to minimize progression to β cell exhaustion before irreversible insulin resistance sets in, with diet, exercise, and treatment with so-called insulin sensitizers (such as metformin and rosiglitazone).
The converse of disorders of hormone deficiency or resistance is seen in diseases associated with hormone excess and/or over-stimulation of hormone receptors. A wide variety of endocrine tumors may produce hormones in an excessive and uncontrolled fashion. Note that the secretion of hormones from tumor cells may not be subject to the same types of feedback regulation that are seen for the normal source of that hormone. In the setting of an endocrine tumor, exaggerated effects of the hormone are seen. For example, acromegaly, or gigantism, occurs in patients afflicted with an adenoma derived from pituitary somatotropes that secretes excessive quantities of growth hormone (see Chapter 18). In addition, other endocrine tumors may secrete hormones other than those characteristic of the cell type or tissue from which they are originally derived. When hormone production is increased in all of these cases, there usually will also be downregulation of upstream releasing factors due to the triggering of negative feedback loops.
Disorders of hormone excess can also be mimicked by antibodies that bind to, and activate, the receptor for the hormone. A classic example of such a condition is Graves’ disease, where susceptible individuals generate thyroid-stimulating immunoglobulins (TSIs) that bind to the receptor for TSH. This causes a conformational change that elicits receptor activation, and thus secretion of thyroid hormone in the absence of a physiological trigger for this event. Diseases associated with hormone excess can also occur in a heritable fashion secondary to activating mutations of hormone releasing factor receptors or their downstream targets. As seen for endocrine tumors, these pathophysiological triggers of excessive hormone release are of course not subject to dampening by negative feedback loops.
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 the relative stability of body systems, that is homeostasis.
Hormones can be grouped into peptide/protein, amine, and steroid categories. 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.
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.
Jameson JL (editor): Harrison’s Endocrinology, 2nd ed. McGraw Hill, 2010.
Lee EK, Gorospe M: Minireview: Posttranslational regulation of the insulin and insulin-like growth factor systems. Endocrinol 2010;151:1403.
Levin ER: Minireview: Extranuclear steroid receptors: Roles in modulation of cell functions. Mol Endocrinol 2011;25:377.
Manna PR, Stocco DM: The role of specific mitogen-activated protein kinase signaling cascades in the regulation of steroidogenesis. J Signal Transduct 2011. Article ID 821615; 13 pp.
Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P: Clinical course of genetic diseases of the insulin receptor (Type A and Rabson-Mendenhall syndromes). A 30-year perspective. Medicine 2004;83:209.
Walker JJ, Terry JR, Tsaneva-Atanasova K, Armstrong SP, McArdle CA, Lightman SL: Encoding and decoding mechanisms of pulsatile hormone secretion. J Neuroendocrinol 2010;22:1226.