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Principles and Practice of Endocrinology and Metabolism



Role of the Endocrine System
Chemical Classification
Sources, Controls, and Functions
Types of Secretory Transport
Overlap of Exocrine and Endocrine Types of Secretion
Tyranny of Hormone Terminology
Endocrine System Interaction with all Body Systems
Genetics and Endocrinology
Normal and Abnormal Expression or Modulation of the Hormonal Message and its Metabolic Effect
The Endocrine Patient
Frequency of Endocrine Disorders
Cost of Endocrine Disorders
Factors that Influence Test Results
Reliability of the Laboratory Determination
Determination of Abnormal Test Results
Risks of Endocrine Testing
Cost and Practicability of Endocrine Testing
Chapter References

Endocrinology is the study of communication and control within a living organism by means of chemical messengers that are synthesized in whole or in part by that organism.
Metabolism, which is an integral part of the science of endocrinology, is the study of the biochemical control mechanisms that occur within living organisms. The term includes such diverse activities as gene expression; biosynthetic pathways and their enzymatic catalysis; the modification, transformation, and degradation of biologic substances; the biochemical mediation of the actions and interactions of such substances; and the means for obtaining, storing, and mobilizing energy.
The chemical messengers of endocrinology are the hormones, endogenous informational molecules that are involved in both intracellular and extracellular communication.
The mammalian organism, including the human, is multicellular and highly specialized with regard to sustaining life and reproductive processes. Reproduction requires gametogenesis, fertilization, and implantation. Subsequently, the new intrauterine conception must undergo cell proliferation, organogenesis, and differentiation into a male or female. After parturition, the newborn must grow and mature sexually, so that the cycle may be repeated. To a considerable extent, the endocrine system influences or controls all of these processes. Hormones participate in all physiologic functions, such as muscular activity, respiration, digestion, hematopoiesis, sense organ function, thought, mood, and behavior. The overall purpose of the coordinating, regulating, integrating, stimulating, suppressing, and modulating effects of the many components of the endocrine system is homeostasis. The maintenance of a healthy optimal internal milieu in the presence of a continuously changing and sometimes threatening external environment is termed allostasis.
Most hormones can be classified into one of several chemical categories: amino-acid derivatives (e.g., tryptophan ® serotonin and melatonin; tyrosine ® dopamine, norepinephrine, epinephrine, triiodothyronine, and thyroxine; L-glutamic acid ® g-aminobutyric acid; histidine ® histamine), peptides or polypeptides (e.g., thyrotropin-releasing hormone, insulin, growth hormone, nerve growth factor), steroids (e.g., progesterone, androgens, estrogens, corticosteroids, vitamin D and its metabolites), and fatty acid derivatives (e.g., prostaglandins, leukotrienes, thromboxanes).
Previously hormones were thought to be synthesized and secreted predominantly by anatomically discrete and circumscribed glandular structures, called ductless glands (e.g., pituitary, thyroid, adrenals, gonads). However, many microscopic organoid-like groups of cells and innumerable other cells of the body contain and secrete hormones (see Chap. 175).
The classic “glands” of endocrinology have lost their exclusivity, and although they are important on physiologic and pathologic levels, the widespread secretion of hormones throughout the body by “nonglandular” tissues is of equal importance. Most hormones are known to have multiple sources. Moreover, the physiologic stimuli that release these hormones are often found to differ according to their locale. The response to a secreted hormone is not stereotyped but varies according to the nature and location of the target cells or tissues.
Hormones have various means of reaching target cells. In the early decades of the development of the field of endocrinology, hormones were conceived to be substances that traveled to distal sites through the blood. This is accomplished by release into the extracellular spaces and subsequent entrance into blood vessels by way of capillary fenestrations. The most appropriate term for such blood-bone communication is hemocrine (Fig. 1-1).

FIGURE 1-1. Different types of hormonal communication detailed in the chapter. The darkened areas on the cell membrane represent receptors. (H, hormone.) See text for explanations.

Several alternative means of hormonal communication exist, however. Paracrine communication involves the extrusion of hormonal contents into the surrounding interstitial spaces; the hormone then interacts with receptors on nearby cells (see Fig. 1-1 and Chap. 4 and Chap. 175).1 Direct paracrine transfer of cytoplasmic messenger molecules into adjacent cells may occur through specialized gap junctions (i.e., intercrine secretion).2 Unlike hemocrine secretion, in which the hormonal secretion is diluted within the circulatory system, paracrine secretion delivers a very high concentration of hormone to its target site. Juxtacrine communication occurs when the messenger molecule does not traverse a fluid phase to reach another cell, but, instead, remains associated with the plasma membrane of the signaling cell while acting directly on an immediately adjacent receptor cell (e.g., intercellular signaling that is adhesion dependent and occurs between endothelial cells and leukocytes and transforming growth factor-a in human endometrium).3,4
Hormones may be secreted and subsequently interact with the same cell that released the substance; this process is autocrine secretion (see Fig. 1-1).5 The secreted hormone stimulates, suppresses, or otherwise modulates the activity of the secreting cell. Autocrine secretion is a form of self-regulation of a cell by its own product.
When peptide hormones or other neurotransmitters or neuromodulators are produced by neurons, the term neurocrine secretion is used (see Fig. 1-1).6 This specialized form of paracrine release may be synaptic (i.e., the messenger traverses a structured synaptic space) or nonsynaptic (i.e., the messenger is carried to its local or distal site of action by way of the extracellular fluid or the blood). Nonsynaptic neurocrine secretion has also been called neurosecretion. An example of neurosecretion is the release of vasopressin and oxytocin into the circulatory system by nervous tissue of the pituitary (see Chap. 25).
Several peptides and amines are secreted into the luminal aspect of the gut (e.g., gastrin, somatostatin, luteinizing hormone– releasing hormone, calcitonin, secretin, vasoactive intestinal peptide, serotonin, substance P).7 This process may be called solinocrine secretion (see Fig. 1-1), from the Greek word for a hollow tube. Solinocrine secretion also occurs into the bronchi, the urogenital tract, and other ductal structures.8
Commonly, the same hormone can be transported by more than one of these means.9
Extracellular transportation may not always be necessary for hormones to exert their effects. For example, some known hormonal secretions that are transported by one or more of these mechanisms are also found in extremely low concentrations within the cytoplasm of many cells. In such circumstances, these hormones do not appear to be localized to identifiable secretion granules and probably act primarily within the cell. This phenomenon may be called intracrine secretion. As shown in Figure 1-1, the process comprising uptake of a hormone precursor H1 and intracellular conversion into H2 (e.g., estrogens) or H3 (e.g., androgens) and subsequent binding and nuclear action is also a form of intracrine communication.
Classically, an exocrine gland is a specialized structure that secretes its products at an external or internal surface (e.g., sweat glands, sebaceous glands, salivary glands, oxyntic or gastric glands, pancreatic exocrine glandular system, prostate gland). An exocrine gland may be unicellular (e.g., mucous or goblet cells of the epithelium of mucous membranes) or multicellular (e.g., salivary glands). Many multicellular exocrine glands possess a structured histologic organization that is suited to the production and delivery of secretions that are produced in relatively large quantities. A specialized excretory duct or system of ducts usually constitutes an intrinsic part of the gland. Some exocrine glandular cells secrete their substances by means of destruction of the cells themselves (i.e., holocrine secretion); an example is the sebaceous glands. Other exocrine glandular cells secrete their substances by way of the loss of a portion of the apical cytoplasm along with the material being secreted (i.e., apocrine secretion); an example is the apocrine sweat glands. Alternatively, in many forms of exocrine secretion, the secretory cells release their products through the cell membrane, and the cell remains intact (i.e., merocrine secretion); an example is the salivary glands. The constituents of some exocrine glands, particularly those opening on the external surface of the body, sometimes function as pheromones, which are chemical substances that act on other members of the species.10
Many exocrine glands contain cells of the diffuse neuroendocrine system (see Chap. 175) and neurons; both cell types secrete peptide hormones. Peptide hormones, steroids, and prostaglandins are found in all exocrine secretions (e.g., sweat, saliva, milk, bile, seminal fluid; see Chap. 106).11,12,13 and 14 Although they usually are not directly produced in such glands, thyroid and steroid hormones are found in exocrine secretions as well.15,16,17 and 18
The preferred approach is to view the term “exocrine” as a histologic-anatomic entity and not as a term that is meant to be antithetical to or to contrast with the term “endocrine.” Endocrinologists are concerned clinically and experimentally with all means of hormonal communication. The word “endocrine” is best used in a global sense, indicating any and all means of communication by messenger molecules.
Hormones usually are named at the time of their discovery. Sometimes, the names are based on the locations where they were first found or on their presumed effects. However, with time, other locations and other effects are discovered, and these new locations or effects often are more physiologically relevant than the initial findings. Hormonal names are often overly restrictive, confusing, or misleading.
In many instances, such hormonal names have become inappropriate. For example, atrial natriuretic hormone is present in the brain, hypothalamus, pituitary, autonomic ganglia, and lungs as well as atrium, and it has effects other than natriuresis (see Chap. 178). Gastrin-releasing peptide is found in semen, far from the site of gastrin release. Somatostatin, which was found in the hypothalamus and named for its inhibitory effect on growth hormone, occurs in many other locations and has multiple other functions (see Chap. 169). Calcitonin, which initially was thought to play an important role in regulating serum calcium and was named accordingly, appears to exert many other effects, and its influence on serum calcium may be quite minor (see Chap. 53). Growth hormone–releasing hormone and arginine vasopressin are found in the testis, where effects on growth hormone release or on the renal tubular reabsorption of water are most unlikely. Vasoactive intestinal peptide is found in multiple tissues other than the intestines (see Chap. 182). Insulin, named for the pancreatic islets, is found in the brain and elsewhere.19 Prostaglandins have effects that are far more widespread than those exerted in the secretions of the prostate, from which their name derives (see Chap. 172).
The endocrine lexicon also contains substances called hormones that are not hormones. In the human, melanocyte-stimulating hormone (MSH) is not a functional hormone, but it comprises amino-acid sequences within the proopiomelanocortin (POMC) molecule: a-MSH within the adrenocorticotropic hormone (ACTH) moiety, b-MSH within d-lipotropin, and d-MSH within the N-terminal fragment of POMC (see Chap. 14).
Numerous peptide hormones exist that, because of their effects on DNA synthesis, cell growth, and cell proliferation, have been called growth factors and cytokines (see Chap. 173 and Chap. 174). These substances, which act locally and at a distance, often do not have the sharply delineated target cell selectivity that was attributed to them when they first were discovered. Their terminology also is confusing and often misleading.
Aside from occasional readjustments of hormonal nomenclature, no facile solution appears to exist to the quandary of terminology, other than an awareness of the pitfalls into which the terms may lead us.
Although speaking in terms of the cardiovascular, respiratory, gastrointestinal, and nervous systems is convenient, the endocrine system anatomically and functionally overlaps with all body systems (see Part X). Extensive overlap is found between the endocrine system and the nervous system (see Chap. 175 and Chap. 176). Hormonal peptides are synthesized in the cell bodies of neurons, are transported along axons to nerve terminals, and are released at the nerve endings. Within these neurons, they coexist with classic neurotransmitters and often are coreleased with them. These substances play a role in neuromodulation or neurosecretion by means of the extracellular fluid. The nerves in which peptide hormones appear to play a role in the transmission of information are called peptidergic nerves.20 It is the ample similarity of ultrastructure, histochemistry, and hormonal contents of nerve cells and of many peptide-secreting endocrine cells that has led to the concept of the diffuse neuroendocrine system.
The rapid application of new discoveries and new techniques in genetics has revolutionized medicine, including the field of endocrinology. DNA probes have been targeted to selected genes, and the chromosomal locations of genes related to many hormones and their receptors have been determined. A complete map of the human genome is gradually emerging.21 This approach has led to new knowledge about hormone biosynthesis and has provided important information concerning species differences and evolution. The elucidation of the chromosomal loci for genes controlling the biosynthesis of hormone receptors should provide insights into the physiologic effects of hormones. Clinically, these techniques have potential significance as a diagnostic aid in evaluating afflicted patients, a means of identifying asymptomatic heterozygotes, and a method for identification of unborn individuals at risk (i.e., prenatal diagnosis; see Chap. 240). Delineation of processes of genetic expression is revealing the mechanisms of hormonal disease (e.g., obesity22) and also may lead to gene therapy for some forms of endocrine illness or humoral-mediated conditions.23
A sophisticated and faultless machinery is required for appropriate hormonal expression. The hormonal messenger is subject to modifications that may occur anywhere from its initial synthesis to its final arrival at its target site. Subsequently, the expression of the message at this site (i.e., its action) may also be modified (see Chap. 4). The modulations or alterations of the hormonal message or its final action may be physiologic or pathologic. Table 1-1 summarizes some of the normal and abnormal modulations of a hormonal message and its subsequent metabolic effects.

TABLE 1-1. Modulation of the Hormone Message and Its Subsequent Physiologic or Pathologic Metabolic Effects

On a physiologic level, the first steps in the genetic ordering of hormonal synthesis, the subsequent posttranslational processing of the hormone, the postsecretory extracellular transport, the receptor mediation of the hormone and subsequent transduction, and the inactivation and clearance of the hormone all contribute to expressing, diversifying, focalizing, and specifying the hormonal message and its ultimate action. On a pathologic level, all of these steps are subject to malfunction, causing disease. Our increased knowledge of endocrine systems has forced us to rethink many traditional concepts. To dispel some common misconceptions, listing several “nots” of endocrinology may be worthwhile (Table 1-2).

TABLE 1-2. Several “Nots” of Modern Endocrinology

In a survey of the subspecialty problems seen by endocrinologists, the six most common, in order of frequency, were found to be diabetes mellitus, thyrotoxicosis, hypothyroidism, nontoxic nodular goiter, diseases of the pituitary gland, and diseases of the adrenal gland. Some conditions seen by endocrinologists are infrequent or rare (e.g., congenital adrenal hyperplasia, pseudohypoparathyroidism), whereas others are relatively common (e.g., Graves disease, Hashimoto thyroiditis), and some are among the most prevalent diseases in general practice (e.g., diabetes mellitus, obesity, hyperlipoproteinemia, osteoporosis, Paget disease). The third most common medical problem encountered by general practitioners is diabetes mellitus, and the tenth most frequent problem is obesity.66
Of the total deaths in the United States (i.e., both sexes, all races, and all ages combined), diabetes mellitus is the seventh most common cause. The most common cause of death (heart disease) and the third most common (cerebrovascular accidents) are greatly influenced by metabolic conditions such as diabetes mellitus and hyperlipemia.67
The frequency and morbidity of endocrine diseases such as osteoporosis, obesity, hypothyroidism, and hyperthyroidism, and the grave consequences of other endocrine disorders such as Cushing syndrome and Addison disease demonstrate that the expense to society is considerable. In the case of diabetes, the health care expenditure is staggering. Approximately 10.3 million people have diabetes in the U.S., and an estimated 5.4 million have undiagnosed diabetes. Direct medical expenses attributed to diabetes total $44.1 billion. The total annual medical expenses of people with diabetes average $10,071 per capita, as compared to $2,669 for persons without diabetes.68 Interestingly, these expenses may be less if the appropriate specialties are involved in the care.69
In clinical medicine, hormonal concentrations usually are ascertained from two of the most easily obtained sources: blood and urine. The diagnosis of an endocrinopathy often depends on the demonstration of increased or decreased levels of these blood or urine constituents. However, several factors must be kept in mind when interpreting a result that appears to be abnormal. These may include age, gender, time of day, exercise, posture, emotional state, hepatic and renal status, presence of other illness, and concomitant drug therapy (see Chap. 237 and Chap. 239).
The practice of clinical endocrinology far from a large medical center was previously hindered by the difficulty in obtaining blood and urine tests essential for appropriate diagnosis and follow-up care. However, accurate and rapid analyses now are provided by commercial laboratories. Nevertheless, wherever performed, some tests are unreliable because of methodologic difficulties. Other tests may be difficult to interpret because of a particular susceptibility to alteration by physiologic or pharmacologic factors (e.g., plasma catecholamines; see Chap. 86). Although many tests are sensitive and specific, they all have innate interassay and intraassay variations that may be particularly misleading when a given value is close to the clinical “medical decision point” (see Chap. 237). Some laboratory differences are due to hormone heterogeneity (e.g., growth hormone has several isoforms, which bind differently to growth hormone–binding proteins).70
Not uncommonly, the intellectual or commercial enthusiasm engendered by a new diagnostic procedure of presumed importance is found to be unjustified, because the “test” was based on an invalid premise, because too few of ill patients were studied, because normative data to establish reference values were insufficient, or because subsequent studies were not confirmatory (see Chap. 237 and Chap. 241).
The increased sophistication of medical testing has made the physician and the patient aware of the presence of “abnormalities” that may be harmless: physiologic deviations from that which is most common, or pathologic entities that commonly remain asymptomatic. Such findings may cause considerable worry, lead to the expense and risk of further diagnostic procedures, and even cause needless therapeutic intervention.
Some “abnormalities” are the result of methods of imaging. For example, sonography of the thyroid may demonstrate the presence of small nodules within the thyroid gland of a person without any palpable abnormality of that region of the gland; most such microlesions are benign or behave as if they were.
Another “abnormality” revealed by imaging is the occasional heterogeneous appearance of a normal pituitary gland on a computed tomography (CT) examination. Intermingled CT-lucent and CT-dense areas are seen on the scan, and such nonhomogeneous areas may be confused with a microadenoma.71,72 The increasing use of magnetic resonance imaging (MRI) of the brain may reveal a bona fide asymptomatic microadenoma of the pituitary gland, but extensive endocrine workup often reveals many such lesions to be nonfunctional. They occur in as much as 10% of the normal population.73
Rathke cleft cysts of the anterior sella turcica or the anterior suprasellar cistern often are seen by MRI.74 Although an occasional patient may have a large and symptomatic lesion,75 most of these lesions are small and asymptomatic. During MRI or CT examination of the brain, the examiner often incidentally encounters a “primary empty sella,” an extension of the subarachnoid space into the sella turcica with a resultant flattening of the pituitary gland in a patient without any pituitary lesion or any prior surgery of that region (see Chap. 11). Although some of these patients may be symptomatic, most have no associated symptoms or hormonal deficit. Another, albeit rare, lesion of the pituitary region seen on MRI is a sellar spine. This asymptomatic anatomic variant is an osseous spine arising in the midline from the dorsum sella that protrudes into the pituitary fossa; it may be an ossified remnant of the cephalic tip of the notochord.76
MRI or CT scanning of the abdomen may reveal the presence of harmless morphologic variations of the adrenal gland (i.e., incidentalomas) that sometimes leads to unnecessary surgery.77 (See Chap. 84.)
Endocrine testing is not always benign. Many procedures can cause mild to marked side effects.78,79,80 and 81 Other diagnostic maneuvers, particularly angiography, may result in severe illness.82 The expected benefit of any procedure that is contemplated for a patient clearly should be greater than the risk.
In addition to being aware of the many factors that influence hormonal values, the limitations of laboratory determinations, and the potential risks of some of these procedures, the endocrinologist must be aware of their expense, particularly because medical costs have increased at an annual rate that is almost twice the rate of overall inflation during the last several years.
A hypertensive patient with hypokalemia who is taking neither diuretics nor laxatives should undergo studies of the renin-angiotensin-aldosterone system, and appropriate pharmacologic or dietary manipulations of sodium balance should be instituted (see Chap. 90). But what should be done with the hypertensive patient who is normokalemic? Occasionally, such a person may have an aldosteronoma.83 Should such normokalemic patients be studied? Similarly, should the approximately 25 million hypertensive patients in the United States undergo urinary collections for determinations of catecholamine metabolites to find the rare patient with pheochromocytoma? In the context of the individual physician-patient relationship, the answers to such questions may not be difficult, but they become more controversial when placed within the framework of fiscal guidelines.
The complexity of the endocrine system presents a profound intellectual challenge. The macrosystem of endocrine glands secretes its hormones under the influence of other gland-based releasing factors or neural influences or both. The very act of secretion alters subsequent secretion by means of feedback controls (see Chap. 5). Superimposed on this already complex arrangement, the microsystem of dispersed, somewhat independent, but overlapping units throughout the body, as well as the continuous modulation of the receptors for the secreted hormones, allow general or focal actions that are coordinated with other body functions, tempered to the occasion, and appropriate to the needs of the individual. That such a complex system may go awry and that a dysfunction may have a considerable impact on the patient is not surprising.
Because endocrinology and metabolism are broad subjects that incorporate much, if not all, of normal body functions and disease states, they defy easy categorization. However, these enormous complexities, rather than deterring the clinician, researcher, or student, should provide a stimulus to probe deeper into areas difficult to understand and should hasten the eventual application of new developments to patient care.

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