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(BQ) Part 2 book Harrison''s endocrinology presents the following contents: Diabetes mellitus, obesity, lipoprotein metabolism; disorders affecting multiple endocrine systems; disorders of bone and calcium metabolism; laboratory values of clinical importance.
SECTION III Diabetes Mellitus, Obesity, Lipoprotein Metabolism CHAPTER 16 BIOLOGY OF OBESITY Jeffrey s Flier ■ eleftheria Maratos-Flier men and women Large-scale epidemiologic studies suggest that all-cause, metabolic, cancer, and cardiovascular morbidity begin to rise (albeit at a slow rate) when BMIs are ≥25, suggesting that the cutoff for obesity should be lowered Most authorities use the term overweight (rather than obese) to describe individuals with BMIs between 25 and 30 A BMI between 25 and 30 should be viewed as medically significant and worthy of therapeutic intervention, especially in the presence of risk factors that are influenced by adiposity such as hypertension and glucose intolerance The distribution of adipose tissue in different anatomic depots also has substantial implications for morbidity Specifically, intraabdominal and abdominal subcutaneous fat have more significance than subcutaneous fat present in the buttocks and lower extremities This distinction is most easily made clinically by determining the waistto-hip ratio, with a ratio >0.9 in women and >1.0 in men being abnormal Many of the most important complications of obesity such as insulin resistance, diabetes, hypertension, hyperlipidemia, and hyperandrogenism in women, are linked more strongly to intraabdominal and/or upper body fat than to overall adiposity (Chap 18) The mechanism underlying this association is unknown but may relate to the fact that intraabdominal adipocytes are more lipolytically active than those from other depots Release of free fatty acids into the portal circulation has adverse metabolic actions, especially on the liver Whether adipokines and cytokines secreted by visceral adipocytes play an additional role in systemic complications of obesity is an area of active investigation In a world where food supplies are intermittent, the ability to store energy in excess of what is required for immediate use is essential for survival Fat cells, residing within widely distributed adipose tissue depots, are adapted to store excess energy efficiently as triglyceride and, when needed, to release stored energy as free fatty acids for use at other sites This physiologic system, orchestrated through endocrine and neural pathways, permits humans to survive starvation for as long as several months However, in the presence of nutritional abundance and a sedentary lifestyle, and influenced importantly by genetic endowment, this system increases adipose energy stores and produces adverse health consequences dEfINITION aNd mEaSuREmENT Obesity is a state of excess adipose tissue mass Although often viewed as equivalent to increased body weight, this need not be the case—lean but very muscular individuals may be overweight by numerical standards without having increased adiposity Body weights are distributed continuously in populations, so that choice of a medically meaningful distinction between lean and obese is somewhat arbitrary Obesity is therefore more effectively defined by assessing its linkage to morbidity or mortality Although not a direct measure of adiposity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2) (Fig 16-1) Other approaches to quantifying obesity include anthropometry (skinfold thickness), densitometry (underwater weighing), CT or MRI, and electrical impedance Using data from the Metropolitan Life Tables, BMIs for the midpoint of all heights and frames among both men and women range from 19 to 26 kg/m2; at a similar BMI, women have more body fat than men Based on data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both PREValENCE Data from the National Health and Nutrition Examination Surveys (NHANES) show that the percentage of the American adult population with obesity (BMI >30) has increased from 14.5% (between 1976 and 1980) to 33.9% (between 2007 and 2008) As many 234 Weight kg lb 150 140 130 120 Height cm in 340 320 300 280 125 Body Mass Index [kg/m2] 50 130 70 260 110 240 WOMEN 60 MEN 135 100 95 220 RELATIVE RISK 50 RELATIVE RISK 140 90 200 190 180 VERY HIGH 145 85 80 75 70 VERY HIGH 40 HIGH HIGH MODERATE MODERATE 170 160 150 140 150 30 LOW 60 155 LOW 160 130 55 120 50 110 170 45 100 175 95 90 180 35 VERY LOW 20 85 80 75 65 60 25 165 65 70 185 10 70 30 VERY LOW 55 50 Figure 16-1 Nomogram for determining body mass index To use this nomogram, place a ruler or other straight edge between the body weight (without clothes) in kilograms or pounds located on the left-hand line and the height (without shoes) in as 68% of U.S adults aged ≥20 years were overweight (defined as BMI >25) between the years of 2007 and 2008 Extreme obesity (BMI ≥40) has also increased and affects 5.7% of the population The increasing prevalence of medically significant obesity raises great concern Obesity is more common among women and in the poor, and among blacks and Hispanics; the prevalence in children is also rising at a worrisome rate Physiologic Regulation of Energy Balance Substantial evidence suggests that body weight is regulated by both endocrine and neural components that ultimately influence the effector arms of energy intake 190 75 195 200 205 80 210 85 centimeters or inches located on the right-hand line The body mass index is read from the middle of the scale and is in metric units (Copyright 1979, George A Bray, MD; used with permission.) and expenditure This complex regulatory system is necessary because even small imbalances between energy intake and expenditure will ultimately have large effects on body weight For example, a 0.3% positive imbalance over 30 years would result in a 9-kg (20-lb) weight gain This exquisite regulation of energy balance cannot be monitored easily by calorie-counting in relation to physical activity Rather, body weight regulation or dysregulation depends on a complex interplay of hormonal and neural signals Alterations in stable weight by forced overfeeding or food deprivation induce physiologic changes that resist these perturbations: with weight loss, appetite increases and energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases This latter compensatory mechanism Biology of Obesity 60 40 55 CHAPTER 16 65 235 236 SECTION III Diabetes Mellitus, Obesity, Lipoprotein Metabolism frequently fails, however, permitting obesity to develop when food is abundant and physical activity is limited A major regulator of these adaptive responses is the adipocyte-derived hormone leptin, which acts through brain circuits (predominantly in the hypothalamus) to influence appetite, energy expenditure, and neuroendocrine function (see below) Appetite is influenced by many factors that are integrated by the brain, most importantly within the hypothalamus (Fig 16-2) Signals that impinge on the hypothalamic center include neural afferents, hormones, and metabolites Vagal inputs are particularly important, bringing information from viscera, such as gut distention Hormonal signals include leptin, insulin, cortisol, and gut peptides Among the latter is ghrelin, which is made in the stomach and stimulates feeding, and peptide YY (PYY) and cholecystokinin, which is made in the small intestine and signal to the brain through direct action on hypothalamic control centers and/or via the vagus nerve Metabolites, including glucose, can influence appetite, as seen by the effect of hypoglycemia to induce hunger; however, glucose is not normally a major regulator of appetite These diverse hormonal, metabolic, and neural signals act by influencing the expression and release of various hypothalamic peptides [e.g., neuropeptide Y (NPY), Agouti-related peptide (AgRP), α-melanocyte-stimulating hormone (α-MSH), and melanin-concentrating hormone (MCH)] that are integrated with serotonergic, catecholaminergic, endocannabinoid, and opioid signaling pathways (see below) Psychological and cultural factors also play a role in the final expression of appetite Apart from rare genetic syndromes involving leptin, its receptor, and the Psychological factors Decrease appetite NPY MCH AgRP Orexin Endocannabinoid Neural afferents (vagal) The Adipocyte and Adipose Tissue Central controllers of appetite Increase Gut peptides CCK Ghrelin PYY melanocortin system, specific defects in this complex appetite control network that influence common cases of obesity are not well defined Energy expenditure includes the following components: (1) resting or basal metabolic rate; (2) the energy cost of metabolizing and storing food; (3) the thermic effect of exercise; and (4) adaptive thermogenesis, which varies in response to long-term caloric intake (rising with increased intake) Basal metabolic rate accounts for ∼70% of daily energy expenditure, whereas active physical activity contributes 5–10% Thus, a significant component of daily energy consumption is fixed Genetic models in mice indicate that mutations in certain genes (e.g., targeted deletion of the insulin receptor in adipose tissue) protect against obesity, apparently by increasing energy expenditure Adaptive thermogenesis occurs in brown adipose tissue (BAT), which plays an important role in energy metabolism in many mammals In contrast to white adipose tissue, which is used to store energy in the form of lipids, BAT expends stored energy as heat A mitochondrial uncoupling protein (UCP-1) in BAT dissipates the hydrogen ion gradient in the oxidative respiration chain and releases energy as heat The metabolic activity of BAT is increased by a central action of leptin, acting through the sympathetic nervous system that heavily innervates this tissue In rodents, BAT deficiency causes obesity and diabetes; stimulation of BAT with a specific adrenergic agonist (β3 agonist) protects against diabetes and obesity BAT exists in humans (especially neonates), and although its physiologic role is not yet established, identification of functional BAT in many adults using PET imaging has increased interest in the implications of the tissue for pathogenesis and therapy of obesity α-MSH CART GLP-1 Serotonin Cultural factors Hormones Leptin Insulin Cortisol Metabolites Glucose Ketones Figure 16-2 The factors that regulate appetite through effects on central neural circuits Some factors that increase or decrease appetite are listed AgRP, Agouti-related peptide; α-MSH, α-melanocyte-stimulating hormone; CART, cocaineand amphetamine-related transcript; CCK, cholecystokinin; GLP-1, glucagon-elated peptide-1; MCH, melanin-concentrating hormone; NPY, neuropeptide Y Adipose tissue is composed of the lipid-storing adipose cell and a stromal/vascular compartment in which cells including preadipocytes and macrophages reside Adipose mass increases by enlargement of adipose cells through lipid deposition, as well as by an increase in the number of adipocytes Obese adipose tissue is also characterized by increased numbers of infiltrating macrophages The process by which adipose cells are derived from a mesenchymal preadipocyte involves an orchestrated series of differentiation steps mediated by a cascade of specific transcription factors One of the key transcription factors is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that binds the thiazolidinedione class of insulin-sensitizing drugs used in the treatment of type diabetes (Chap 19) Although the adipocyte has generally been regarded as a storage depot for fat, it is also an endocrine cell that releases numerous molecules in a regulated fashion (Fig. 16-3) These include the energy balance–regulating Specific genetic syndromes Although the molecular pathways regulating energy balance are beginning to be illuminated, the causes of obesity remain elusive In part, this reflects the fact that obesity is a heterogeneous group of disorders At one level, the pathophysiology of obesity seems simple: a chronic excess of nutrient intake relative to the level of energy expenditure However, due to the complexity of the neuroendocrine and metabolic systems that regulate energy intake, storage, and expenditure, it has been difficult to quantitate all the relevant parameters (e.g., food intake and energy expenditure) over time in human subjects For many years, obesity in rodents has been known to be caused by a number of distinct mutations distributed through the genome Most of these single-gene mutations cause both hyperphagia and diminished energy expenditure, suggesting a physiologic link between these two parameters of energy homeostasis Identification of the ob gene mutation in genetically obese (ob/ ob) mice represented a major breakthrough in the field The ob/ob mouse develops severe obesity, insulin resistance, and hyperphagia, as well as efficient metabolism (e.g., it gets fat even when ingesting the same number of calories as lean litter mates) The product of the ob gene is the peptide leptin, a name derived from the Greek root leptos, meaning thin Leptin is secreted by adipose cells and acts primarily through the hypothalamus Its level of production provides an index of adipose energy stores (Fig 16-4) High leptin levels decrease food intake and increase energy expenditure Another mouse mutant, db/db, which is resistant to leptin, has a mutation in the leptin receptor and develops a similar syndrome The ob gene is present in humans where it is also expressed in fat Several families with morbid, early-onset obesity caused by inactivating mutations in Adipocyte Others PAI-1 Angiotensinogen RBP4 Enzymes Aromatase 11-HSD-1 Cytokines TFN-␣ IL-6 Substrates Free fatty acids Glycerol Figure 16-3 Factors released by the adipocyte that can affect peripheral tissues PAI, plasminogen activator inhibitor; RBP4, retinal binding protein 4; TNF, tumor necrosis factor Role of genes versus environment Obesity is commonly seen in families, and the heritability of body weight is similar to that for height Inheritance is usually not Mendelian, however, and it is difficult to distinguish the role of genes and environmental factors Adoptees more closely resemble their biologic than adoptive parents with respect to obesity, providing strong support for genetic influences Likewise, identical twins have very similar BMIs whether reared together 237 Biology of Obesity Etiology of Obesity Hormones Leptin Adiponectin Resistin CHAPTER 16 hormone leptin, cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, complement factors such as factor D (also known as adipsin), prothrombotic agents such as plasminogen activator inhibitor I, and a component of the blood pressure–regulating system, angiotensinogen Adiponectin, an abundant adipose-derived protein whose levels are reduced in obesity, enhances insulin sensitivity and lipid oxidation and it has vascularprotective effects, whereas resistin and retinal binding protein (RBP4), whose levels are increased in obesity, may induce insulin resistance These factors, and others not yet identified, play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, coagulation, and vascular health, and are likely to contribute to obesity-related pathologies or apart, and their BMIs are much more strongly correlated than those of dizygotic twins These genetic effects appear to relate to both energy intake and expenditure Whatever the role of genes, it is clear that the environment plays a key role in obesity, as evidenced by the fact that famine prevents obesity in even the most obesityprone individual In addition, the recent increase in the prevalence of obesity in the United States is far too rapid to be due to changes in the gene pool Undoubtedly, genes influence the susceptibility to obesity in response to specific diets and availability of nutrition Cultural factors are also important—these relate to both availability and composition of the diet and to changes in the level of physical activity In industrial societies, obesity is more common among poor women, whereas in underdeveloped countries, wealthier women are more often obese In children, obesity correlates to some degree with time spent watching television Although the role of diet composition in obesity continues to generate controversy, it appears that high-fat diets may promote obesity when combined with diets rich in simple, rapidly absorbed carbohydrates Additional environmental factors may contribute to the increasing obesity prevalence Both epidemiologic correlations and experimental data suggest that sleep deprivation leads to increased obesity Changes in gut microbiome with capacity to alter energy balance are receiving experimental support from animal studies, and a possible role for obesigenic viral infections continues to receive sporadic attention Complement factors Factor D/adipsin 238 Brain Hypothalamus Glucose and lipid metabolism Hunger/satiety Thermogenesis/autonomic system Neuroendocrine function Blood-brain barrier Beta cells Peripheral targets Immune cells Others Leptin Fed state/obesity SECTION III Adipocyte Leptin Fasted state Diabetes Mellitus, Obesity, Lipoprotein Metabolism Figure 16-4 The physiologic system regulated by leptin Rising or falling leptin levels act through the hypothalamus to influence appetite, energy expenditure, and neuroendocrine function and through peripheral sites to influence systems such as the immune system either leptin or the leptin receptor have been described, thus demonstrating the biologic relevance of the leptin pathway in humans Obesity in these individuals begins shortly after birth, is severe, and is accompanied by neuroendocrine abnormalities The most prominent of these is hypogonadotropic hypogonadism, which is reversed by leptin replacement in the leptin-deficient subset Central hypothyroidism and growth retardation are seen in the mouse model, but their occurrence in leptin-deficient humans is less clear To date, there is no evidence that mutations in the leptin or leptin receptor genes play a prominent role in common forms of obesity Mutations in several other genes cause severe obesity in humans (Table 16-1); each of these syndromes is rare Mutations in the gene encoding proopiomelanocortin (POMC) cause severe obesity through failure to synthesize α-MSH, a key neuropeptide that inhibits appetite in the hypothalamus The absence of POMC also causes secondary adrenal insufficiency due to absence of adrenocorticotropic hormone (ACTH), as well as pale skin and red hair due to absence of α-MSH Proenzyme convertase (PC-1) mutations are thought to cause obesity by preventing synthesis of α-MSH from its precursor peptide, POMC α-MSH binds to the type melanocortin receptor (MC4R), a key hypothalamic receptor that inhibits eating Heterozygous loss-of-function mutations of this receptor account for as much as 5% of severe obesity These five genetic defects define a pathway through which leptin (by stimulating POMC and increasing α-MSH) restricts food intake and limits weight (Fig 16-5) The results Table 16-1 Some Obesity Genes in Humans and Mice Gene Gene Product Mechanism of Obesity In Human In Rodent Lep (ob) Leptin, a fat-derived hormone Mutation prevents leptin from delivering satiety signal; brain perceives starvation Yes Yes LepR (db) Leptin receptor Same as above Yes Yes POMC Proopiomelanocortin, a precursor of several hormones and neuropeptides Mutation prevents synthesis of melanocyte-stimulating hormone (MSH), a satiety signal Yes Yes MC4R Type receptor for MSH Mutation prevents reception of satiety signal from MSH Yes Yes AgRP Agouti-related peptide, a neuropeptide expressed in the hypothalamus Overexpression inhibits signal through MC4R No Yes PC-1 Prohormone convertase 1, a processing enzyme Mutation prevents synthesis of neuropeptide, probably MSH Yes No Fat Carboxypeptidase E, a processing enzyme Same as above No Yes Tub Tub, a hypothalamic protein of unknown function Hypothalamic dysfunction No Yes TrkB TrkB, a neurotrophin receptor Hyperphagia due to uncharacterized hypothalamic defect Yes Yes Leptin Leptin receptor signal Known mutations in man Proopiomelanocortin (POMC) expression AgRP ␣-MSH Melanocortin receptor signal Decreased appetite Figure 16-5 A central pathway through which leptin acts to regulate appetite and body weight Leptin signals through proopiomelanocortin (POMC) neurons in the hypothalamus to induce increased production of α-melanocyte-stimulating hormone (α-MSH), requiring the processing enzyme PC-1 (proenzyme convertase 1) α-MSH acts as an agonist on melanocortin-4 receptors to inhibit appetite, and the neuropeptide AgRp (Agouti-related peptide) acts as an antagonist of this receptor Mutations that cause obesity in humans are indicated by the solid green arrows 239 Other specific syndromes associated with obesity Cushing’s syndrome Although obese patients commonly have central obesity, hypertension, and glucose intolerance, they lack other specific stigmata of Cushing’s syndrome (Chap. 5) Nonetheless, a potential diagnosis of Cushing’s syndrome is often entertained Cortisol production and urinary metabolites (17OH steroids) may be increased in simple obesity Unlike in Cushing’s syndrome, however, cortisol levels in blood and urine in the basal state and in response to corticotropin-releasing hormone (CRH) or ACTH are normal; the overnight 1-mg dexamethasone suppression test is normal in 90%, with the remainder being normal on a standard 2-day lowdose dexamethasone suppression test Obesity may be associated with excessive local reactivation of cortisol in fat by 11β-hydroxysteroid dehydrogenase 1, an enzyme that converts inactive cortisone to cortisol Hypothyroidism The possibility of hypothyroidism should be considered, but it is an uncommon cause of obesity; hypothyroidism is easily ruled out by measuring thyroid-stimulating hormone (TSH) Much of the weight gain that occurs in hypothyroidism is due to myxedema (Chap 4) Insulinoma Patients with insulinoma often gain weight as a result of overeating to avoid hypoglycemic symptoms (Chap 20) The increased substrate plus high insulin levels promote energy storage in fat This can be marked in some individuals but is modest in most raniopharyngioma and other disorders C involving the hypothalamus Whether through tumors, trauma, or inflammation, hypothalamic dysfunction of systems controlling satiety, hunger, and energy expenditure can cause varying degrees of obesity (Chap 2) It is uncommon to Biology of Obesity of genomewide association studies to identify genetic loci responsible for obesity in the general population have so far been disappointing More than 10 replicated loci linked to obesity have been identified, but together they account for less than 3% of interindividual variation in BMI The most replicated of these is a gene named FTO, which is of unknown function, but like many of the other recently described candidates, is expressed in the brain Since the heritability of obesity is estimated to be 40–70%, it is likely that many more loci remain to be identified In addition to these human obesity genes, studies in rodents reveal several other molecular candidates for hypothalamic mediators of human obesity or leanness The tub gene encodes a hypothalamic peptide of unknown function; mutation of this gene causes lateonset obesity The fat gene encodes carboxypeptidase E, a peptide-processing enzyme; mutation of this gene is thought to cause obesity by disrupting production of one or more neuropeptides AgRP is coexpressed with NPY in arcuate nucleus neurons AgRP antagonizes α-MSH action at MC4 receptors, and its overexpression induces obesity In contrast, a mouse deficient in the peptide MCH, whose administration causes feeding, is lean A number of complex human syndromes with defined inheritance are associated with obesity (Table 16-2) Although specific genes have limited definition at present, their identification will likely enhance our understanding of more common forms of human obesity In the Prader-Willi syndrome, a multigenic neurodevelopmental disorder, obesity coexists with short stature, mental retardation, hypogonadotropic hypogonadism, hypotonia, small hands and feet, fish-shaped mouth, and hyperphagia Most patients have a deletion in the 15q11-13 chromosomal region, and reduced expression of the signaling protein necdin may be an important cause of defective hypothalamic neural development in this disorder Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by obesity, mental retardation, retinitis pigmentosa, diabetes, renal and cardiac malformations, polydactyly, and hypogonadotropic hypo gonadism At least 12 genetic loci have been identified, and most of the encoded proteins form two multiprotein complexes that are involved in ciliary function and microtubule-based intracellular transport Recent evidence suggests that mutations might disrupt leptin receptor trafficking in key hypothalamic neurons, causing leptin resistance CHAPTER 16 PC-1 processing enzyme 240 Table 16-2 A Comparison of Syndromes of Obesity—Hypogonadism and Mental Retardation Syndrome Feature Prader-Willi Laurence-Moon-Biedl Ahlstrom’s Cohen’s Carpenter’s Inheritance Sporadic; twothirds have defect Short Autosomal recessive Normal; infrequently short Autosomal recessive Normal; infrequently short Probably autosomal recessive Short or tall Autosomal recessive Normal Obesity Generalized Moderate to severe Onset 1–3 years Generalized Early onset, 1–2 years Truncal Early onset, 2–5 years Truncal Mid-childhood, age Truncal, gluteal Craniofacies Narrow bifrontal diameter Almond-shaped eyes Strabismus V-shaped mouth High-arched palate Not distinctive Not distinctive High nasal bridge Arched palate Open mouth Short philtrum Acrocephaly Flat nasal bridge High-arched palate Limbs Small hands and feet Hypotonia Polydactyly No abnormalities Hypotonia Narrow hands and feet Polydactyly Syndactyly Genu valgum Reproductive status 1° Hypogonadism 1° Hypogonadism Hypogonadism in males but not in females Normal gonadal function or hypogonadotrophic hypogonadism 2° Hypogonadism Other features Enamel hypoplasia Hyperphagia Temper tantrums Nasal speech Mental retardation Mild to moderate Stature SECTION III Diabetes Mellitus, Obesity, Lipoprotein Metabolism identify a discrete anatomic basis for these disorders Subtle hypothalamic dysfunction is probably a more common cause of obesity than can be documented using currently available imaging techniques Growth hormone (GH), which exerts lipolytic activity, is diminished in obesity and is increased with weight loss Despite low GH levels, insulin-like growth factor (IGF)-I (somatomedin) production is normal, suggesting that GH suppression is a compensatory response to increased nutritional supply Pathogenesis of common obesity Obesity can result from increased energy intake, decreased energy expenditure, or a combination of the two Thus, identifying the etiology of obesity should involve measurements of both parameters However, it is difficult to perform direct and accurate measurements Dysplastic ears Delayed puberty Normal intelligence Mild Slight of energy intake in free-living individuals, and the obese, in particular, often underreport intake Measurements of chronic energy expenditure are possible using doubly labeled water or metabolic chamber/rooms In subjects at stable weight and body composition, energy intake equals expenditure Consequently, these techniques allow assessment of energy intake in free-living individuals The level of energy expenditure differs in established obesity, during periods of weight gain or loss, and in the pre- or postobese state Studies that fail to take note of this phenomenon are not easily interpreted There is continued interest in the concept of a body weight “set point.” This idea is supported by physiologic mechanisms centered around a sensing system in adipose tissue that reflects fat stores and a receptor, or “adipostat,” that is in the hypothalamic centers When fat stores are depleted, the adipostat signal is low, and the hypothalamus responds by stimulating hunger and decreasing energy expenditure to conserve energy Conversely, when fat stores are abundant, the signal is increased, and the hypothalamus responds by decreasing hunger and increasing energy expenditure The recent discovery of the ob gene, and its product leptin, and the db gene, whose product is the leptin receptor, provides important elements of a molecular basis for this physiologic concept (see section “Specific Genetic Syndromes”) What is the status of food intake in obesity? (Do the obese eat more than the lean?) The average total daily energy expenditure is higher in obese than lean individuals when measured at stable weight However, energy expenditure falls as weight is lost, due in part to loss of lean body mass and to decreased sympathetic nerve activity When reduced to near-normal weight and maintained there for awhile, (some) obese individuals have lower energy expenditure than (some) lean individuals There is also a tendency for those who will develop obesity as infants or children to have lower resting energy expenditure rates than those who remain lean The physiologic basis for variable rates of energy expenditure (at a given body weight and level of energy intake) is essentially unknown A mutation in the human β3-adrenergic receptor may be associated with increased risk of obesity and/or insulin resistance in certain (but not all) populations One recently described component of thermogenesis, called nonexercise activity thermogenesis (NEAT), has been linked to obesity It is the thermogenesis that accompanies physical activities other than volitional exercise such as the activities of daily living, fidgeting, spontaneous muscle contraction, and maintaining posture NEAT Leptin in typical obesity The vast majority of obese persons have increased leptin levels but not have mutations of either leptin or its receptor They appear, therefore, to have a form of functional “leptin resistance.” Data suggesting that some individuals produce less leptin per unit fat mass than others or have a form of relative leptin deficiency that predisposes to obesity are at present contradictory and unsettled The mechanism for leptin resistance, and whether it can be overcome by raising leptin levels or combining leptin with other treatments in a subset of obese individuals, is not yet established Some data suggest that leptin may not effectively cross the blood-brain barrier as levels rise It is also apparent from animal studies that leptin signaling inhibitors, such as SOCS3 and PTP1b, are involved in the leptin-resistant state Pathologic Consequences of Obesity (See also Chap 17) Obesity has major adverse effects on health Obesity is associated with an increase in mortality, with a 50–100% increased risk of death from all causes compared to normal-weight individuals, mostly due to cardiovascular causes Obesity and overweight together are the second leading cause of preventable death in the United States, accounting for 300,000 deaths per year Mortality rates rise as obesity increases, particularly when obesity is associated with increased intraabdominal fat (see section “Definition and Measurement”) Life expectancy of a moderately obese individual could be shortened by 2–5 years, and a 20- to 30-year-old male with a BMI >45 may lose 13 years of life It is also apparent that the degree to which obesity affects particular organ systems is influenced by susceptibility genes that vary in the population Insulin resistance and type diabetes mellitus Hyperinsulinemia and insulin resistance are pervasive features of obesity, increasing with weight gain and diminishing with weight loss (Chap 18) Insulin resistance is more strongly linked to intraabdominal fat than to fat in other depots Molecular links between obesity and insulin resistance in fat, muscle, and liver have been sought for many years Major factors include (1) insulin itself, by inducing receptor downregulation; (2) free fatty acids that are increased and Biology of Obesity What is the state of energy expenditure in obesity? 241 CHAPTER 16 This question has stimulated much debate, due in part to the methodologic difficulties inherent in determining food intake Many obese individuals believe that they eat small quantities of food, and this claim has often been supported by the results of food intake questionnaires However, it is now established that average energy expenditure increases as individuals get more obese, due primarily to the fact that metabolically active lean tissue mass increases with obesity Given the laws of thermodynamics, the obese person must therefore eat more than the average lean person to maintain their increased weight It may be the case, however, that a subset of individuals who are predisposed to obesity have the capacity to become obese initially without an absolute increase in caloric consumption accounts for about two-thirds of the increased daily energy expenditure induced by overfeeding The wide variation in fat storage seen in overfed individuals is predicted by the degree to which NEAT is induced The molecular basis for NEAT and its regulation is unknown 242 SECTION III capable of impairing insulin action; (3) intracellular lipid accumulation; and (4) several circulating peptides produced by adipocytes, including the cytokines TNF-α and IL-6, RBP4, and the “adipokines” adiponectin and resistin that have altered expression in obese adipocytes and can modify insulin action Additional mechanisms are obesity-linked inflammation, including infiltration of macrophages into tissues including fat, and induction of the endoplasmic reticulum stress response that can bring about resistance to insulin action in cells Despite the prevalence of insulin resistance, most obese individuals not develop diabetes, suggesting that diabetes requires an interaction between obesity-induced insulin resistance and other factors such as impaired insulin secretion (Chap 19) Obesity, however, is a major risk factor for diabetes, and as many as 80% of patients with type diabetes mellitus are obese Weight loss and exercise, even of modest degree, increase insulin sensitivity and often improve glucose control in diabetes Reproductive disorders Diabetes Mellitus, Obesity, Lipoprotein Metabolism Disorders that affect the reproductive axis are associated with obesity in both men and women Male hypogonadism is associated with increased adipose tissue, often distributed in a pattern more typical of females In men whose weight is >160% ideal body weight (IBW), plasma testosterone and sex hormone–binding globulin (SHBG) are often reduced, and estrogen levels (derived from conversion of adrenal androgens in adipose tissue) are increased (Chap 8) Gynecomastia may be seen However, masculinization, libido, potency, and spermatogenesis are preserved in most of these individuals Free testosterone may be decreased in morbidly obese men whose weight is >200% IBW Obesity has long been associated with menstrual abnormalities in women, particularly in women with upper body obesity (Chap 10) Common findings are increased androgen production, decreased SHBG, and increased peripheral conversion of androgen to estrogen Most obese women with oligomenorrhea have the polycystic ovarian syndrome (PCOS), with its associated anovulation and ovarian hyperandrogenism; 40% of women with PCOS are obese Most nonobese women with PCOS are also insulin resistant, suggesting that insulin resistance, hyperinsulinemia, or the combination of the two are causative or contribute to the ovarian pathophysiology in PCOS in both obese and lean individuals In obese women with PCOS, weight loss or treatment with insulin-sensitizing drugs often restores normal menses The increased conversion of androstenedione to estrogen, which occurs to a greater degree in women with lower body obesity, may contribute to the increased incidence of uterine cancer in postmenopausal women with obesity Cardiovascular disease The Framingham Study revealed that obesity was an independent risk factor for the 26-year incidence of cardiovascular disease in men and women [including coronary disease, stroke, and congestive heart failure (CHF)] The waist-to-hip ratio may be the best predictor of these risks When the additional effects of hypertension and glucose intolerance associated with obesity are included, the adverse impact of obesity is even more evident The effect of obesity on cardiovascular mortality in women may be seen at BMIs as low as 25 Obesity, especially abdominal obesity, is associated with an atherogenic lipid profile; with increased low-density lipoprotein cholesterol, very low density lipoprotein, and triglyceride; and with decreased high density lipoprotein cholesterol and decreased levels of the vascular protective adipokine adiponectin (Chap 21) Obesity is also associated with hypertension Measurement of blood pressure in the obese requires use of a larger cuff size to avoid artifactual increases Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss Pulmonary disease Obesity may be associated with a number of pulmonary abnormalities These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased functional residual capacity and expiratory reserve volume Severe obesity may be associated with obstructive sleep apnea and the “obesity hypoventilation syndrome” with attenuated hypoxic and hypercapnic ventilatory responses Sleep apnea can be obstructive (most common), central, or mixed and is associated with hypertension Weight loss (10–20 kg) can bring substantial improvement, as can major weight loss following gastric bypass or restrictive surgery Continuous positive airway pressure has been used with some success Hepatobiliary disease Obesity is frequently associated with the common disorder nonalcoholic fatty liver disease (NAFLD) This hepatic fatty infiltration of NAFLD can progress in a subset to inflammatory nonalcoholic steatohepatitis (NASH) and more rarely to cirrhosis and hepatocellular carcinoma Steatosis has been noted to improve following weight loss, secondary to diet or bariatric surgery The mechanism for the association remains unclear Obesity is associated with enhanced biliary secretion of Index Gonadotropin(s), 46 See also Follicle-stimulating hormone (FSH); Luteinizing hormone (LH) action of, 46 for age-related reproductive dysfunction, 164 deficiency of, 46–47 acquired causes of, 158–159 congenital disorders associated with, 155t, 157–158 treatment of, 47 in male reproductive function, 152 for ovulatory dysfunction, 189 pituitary tumor production of, 47–48 synthesis of, 46 Gonadotropin-releasing hormone (GnRH) agonists, 46, 487, 504 agonist test, 212 defective synthesis of See Kallmann syndrome for hypogonadism, 47 hypothalamic, 17–18, 18f, 46 in ovarian function regulation, 180–181, 181f receptor mutations, 158 stimulation test, 152–153 Gorlin’s syndrome (nevoid basal cell carcinoma syndrome), 218 Gout, obesity and, 244 GPIHP1 deficiency, 322t, 326 G protein(s), 5f, G protein–coupled receptors (GPCRs), 2–3, 2t, 5–6 GRA (glucocorticoid-remediable aldosteronism), 112, 114–115 Graffian follicle, 180f Granuloma annulare, 288 Granulomatous thyroiditis, 84–85 Granulosa cell tumor, of ovary, 218 Graves’ disease, 77 in children, 83 clinical course of, 81 clinical features of, 78–80, 78t, 79f, 88 differential diagnosis of, 80–81 epidemiology of, 77–78 hyperthyroidism of, 81–82 laboratory evaluation of, 80, 80f, 490, 508 pathogenesis of, 78 prevalence of, 13t remission rates, 81, 82 screening and assessment of, 13t thyrotoxic crisis in, 83 treatment of antithyroid drugs, 81–82, 491, 508 in pregnancy, 83 propranolol, 82 radioiodine, 82 thyroidectomy, 82–83 Graves’ ophthalmopathy, 79, 79f, 83, 491, 508 GRFomas (growth hormone–releasing factor tumors), 344t, 359 Growth disorders of, 36–37 hormones in, somatic, skeletal maturation and, Growth hormone (GH), 34 action of, 35 ectopic production of, 377t insensitivity to, 36–37 laboratory evaluation of, 22t in osteoporosis management/prevention, 457 secretion of, 35 signal transduction pathway for, 2t synthesis of, 34–35 Growth hormone (GH) deficiency in adults clinical features of, 37, 38t, 488, 505 diagnosis of, 37–38, 38t treatment of, 23t, 38–39, 39f in children clinical features of, 37 laboratory evaluation of, 37 pathophysiology of, 36–37 treatment of, 23t, 37 idiopathic, 36 Growth hormone (GH) receptor antagonists, for acromegaly, 42 Growth hormone–releasing factor tumors (GRFomas), 344t, 359 Growth hormone-releasing hormone (GHRH), 35, 377t agonists, 226, 227t, 230t receptor mutations, 36 Growth plate, inadequate mineralization of, 400 Guanethidine, adverse effects of, 227t Gynecomastia, 161 in cirrhosis, 160 etiology of, 161–162, 496, 514, 515 evaluation of, 13t, 161–162, 162f, 495, 514 in Klinefelter syndrome, 139, 159 obesity and, 242 pathologic, 161–162, 162f prevalence of, 13t, 161 treatment of, 139, 162 H6PDH (hexose-6-phosphate dehydrogenase), 104 Hair growth cycle of, 209 removal, 213 terminal, 209 vellus, 209 Half-life, circulating hormone, Hamartoma, hypothalamic, 25 Hand-Schüller-Christian disease, 25 Hashimoto’s thyroiditis, 72, 86, 88 Haversian systems, 384, 386 hCG See Human chorionic gonadotropin (hCG) HDL See High-density lipoprotein (HDL) Head and neck cancer, paraneoplastic syndromes in, 377t Heart disease See Cardiovascular disease Heat therapy, for dysmenorrhea, 199 Hemangiopericytoma, 377t Hematocrit, normal, 473t Hematologic disease, reference values, 471–474t 535 Hematopoietic stem cell transplantation (HSCT), for osteopetrosis, 464 Hemochromatosis, hypogonadism and, 159 Hemodialysis for hypercalcemia, 427t, 429 of malignancy, 378 for hypermagnesemia, 396 Hemoglobin normal, 473t testosterone therapy and, 169–170 Hemoglobin A1c, in diabetes mellitus, 290, 290t, 293–294 Heparin, monitoring treatment with, 472t Hepatic artery embolization, for carcinoid syndrome, 353, 362 Hepatic lipase deficiency, familial, 322t, 326 Hepatitis C virus (HCV) infection, osteosclerosis and, 466 Hepatocellular carcinoma (HCC), paraneoplastic syndromes in, 377t Hepatocyte nuclear transcription factor (HNF), 272 Hereditary nonpolyposis colon cancer (HNPCC) endometrial cancer in, 221–222 ovarian cancer in, 216 type II, 216 Hermaphroditism See Ovotesticular disorders of sexual development HESX1 gene, 19, 120t Heterosexual precocity, 154, 186 Hexose-6-phosphate dehydrogenase (H6PDH), 104 HHS (hyperglycemic hyperosmolar state) See Hyperglycemic hyperosmolar state (HHS) High-density lipoprotein (HDL) composition of, 317, 317f high levels of, 327t, 330 low levels of, 327t, 329–330 See also Lipoprotein disorders in metabolic syndrome, 256 metabolism of, 320–321, 320f therapy to increase levels of, 259, 339 Hip fracture, 439–440, 439f Hirsutism, 209 after menopause, 212 approach to the patient, 13t, 209–210, 212f drug-induced, 210, 210t etiology of, 210t hormonal evaluation in, 210–213 in 21-hydroxylase deficiency, 145 prevalence of, 13t scoring scale of Ferriman and Gallwey, 210, 211f treatment of, 213–214 Histamine H2 receptor antagonists, 227t Histiocytosis X, 20, 25 HIV infection, lipodystrophy in, 254 HMG-CoA reductase inhibitors See Statins HNF (hepatocyte nuclear transcription factor), 272 Homeostasis, 7–8 536 Hormone(s) See also specific hormones and types autocrine regulation of, classes of, deficiency of, 11 degradation of, 4–5 ectopic production of, 375–376, 377t endocrine testing related to, 12 eutopic production of, 375 feedback regulatory systems, 8–9, 9f functions of, 7–8 half-life of, measurements of, 12 nature of, paracrine regulation of, resistance to, 11, 487, 504 rhythmic patterns of, 9–10 role of, secretion of, synthesis and processing of, 3–4 transport of, 4–5 Hormone receptors characterization of, 2–3 families of, 2–3, 2t membrane receptors, 5–6, 5f nuclear receptors, 6–7, 7f Hormone replacement therapy for hypopituitarism, 21, 23t postmenopausal See Postmenopausal hormone therapy Hormone resistance syndromes, 11 Howship’s lacunae, 386, 415 HPT-JT (hyperparathyroidism jaw tumor) syndrome, 412, 414 HRPT2 gene, 409–410, 409f Human chorionic gonadotropin (hCG) ectopic production of, 375, 377t, 380–381 in germ cell tumors, 219 in gestational trophoblastic disease, 223 reference values, 478t stimulation test, 153 in testicular cancer, 173 Human menopausal gonadotropin (hMG), for gonadotropin deficiency, 164 Human papillomavirus (HPV), 220 infections cervical cancer and, 220 global considerations, 219 vaccine, 220 Humoral hypercalcemia of malignancy, 421 See also Hypercalcemia, malignancyassociated Hunger, 236 Hydrocortisone for ACTH deficiency, 43 for adrenal insufficiency, 123–124 for CAH, 125, 146 for hypercalcemia, 404 for myxedema coma, 77 Hydroxychloroquine, for hypercalcemia, 404 21-Hydroxylase deficiency classic See Congenital adrenal hyperplasia (CAH) classic simple virilizing, 145 clinical features of, 125t, 145, 146t Index diagnosis of, 213 diagnostic markers of, 125t salt-wasting, 145 17-Hydroxyprogesterone, in CAH, 126 Hymen, imperforate, 195 Hyperaldosteronism glucocorticoid-remediable, 112, 114–115 mineralocorticoid excess in See Mineralocorticoid excess Hyperalphalipoproteinemia, familial, 330 Hyperandrogenism, ovarian, 212 Hyperapobetalipoproteinemia, 328 Hypercalcemia, 402, 410 aluminum intoxication and, 424 asymptomatic, 425 bone turnover–associated, 423 chronic, 425, 425f in chronic kidney disease, 423–424 clinical features of, 403, 411 diagnosis of, 403–404, 411, 425–426, 425f differential diagnosis of, 411, 425–426, 425f etiology of, 402, 403t, 411, 411t, 426, 504, 526 familial benign, 419 familial hypocalciuric, 402, 419 hyperthyroidism and, 423 idiopathic, of infancy, 422–423 immobilization and, 423 lithium and, 418–419 malignancy-associated, 376, 377t, 411t clinical features of, 376 clinical syndromes related to, 420–421 diagnosis of, 376, 421 etiology of, 376, 518–519 mechanisms of, 421 treatment of, 378, 421–422, 499, 504, 518–519, 525 milk-alkali syndrome and, 424–425 in Paget’s disease of bone, 462 primary hyperparathyroidism and See Hyperparathyroidism, primary in sarcoidosis, 422 thiazides and, 423 treatment of, 404, 411, 426, 427t bisphosphonates, 404, 427–428 calcitonin, 428 dialysis, 429 diuresis, 427 gallium nitrate, 428 glucocorticoids, 404, 428 hydration, 404, 426–427 increased salt intake, 427 phosphate therapy, 429 plicamycin, 428 vitamin A intoxication and, 423 vitamin D–related, 422 Hypercalciuria hypocalcemic, 431 in Paget’s disease of bone, 462 Hypercholesterolemia See also Lipoprotein disorders autosomal dominant, 322t, 324 autosomal recessive, 322t, 324 familial, 322–324, 322t polygenic, 325 Hyperemesis gravidarum, 88 Hyperglycemic hyperosmolar state (HHS) clinical features of, 276 laboratory evaluation of, 272t, 276, 511 pathophysiology of, 276 treatment of, 276–277 Hypergonadotropic hypogonadism, 197 Hyperinsulinemia in hirsutism, 210 insulin resistance and, 271 obesity and, 241–242 Hyperinsulinism, endogenous, 308t, 314–315 Hyperlipidemia See Lipoprotein disorders Hyperlipoproteinemia See Lipoprotein disorders Hypermagnesemia, 396 clinical features of, 396 etiology of, 396 laboratory findings in, 396 treatment of, 396 Hypernatremia, adipsic, 56–58, 57f Hyperostosis corticalis generalisata, 465 Hyperparathyroidism asymptomatic, 411–412, 414 hereditary, 412 osteitis fibrosa cystica in, 414–415 prevalence of, 13t primary, 411 clinical features of, 414–416, 519 diagnosis of, 415t, 416, 416f, 425f, 499, 519 etiology of, 411t, 412, 519 genetic factors in, 413–414, 413f incidence of, 412 magnesium deficiency in, 418 in MEN syndromes, 364, 368, 371, 412 natural history of, 412 pathology of, 412 PTH levels in, 416, 416f solitary adenomas and, 412 treatment of medical, 418 in MEN syndromes, 366–367, 371 monitoring in, 415t surgical, 415t, 417–418 screening and assessment of, 13t secondary in chronic kidney disease, 423–424 clinical features of, 423–424 etiology of, 404t hypocalcemia and, 404t pathogenesis of, 424 treatment of, 424 tertiary, 424, 499, 518 Hyperparathyroidism jaw tumor (HPT-JT) syndrome, 412, 414 Hyperparathyroid-like syndromes, 419–420 Hyperphosphatemia, 393 in chronic kidney disease, 433 clinical features of, 393–394 etiology of, 393, 393t hypocalcemia and, 436 severe acute, 436 treatment of, 394 Index Hyperpigmentation, in adrenal insufficiency, 121, 122f Hyperprolactinemia, 30 clinical features of, 31 diagnosis of, 31, 32, 228 erectile dysfunction in, 226 etiology of, 30–31, 31t, 488, 505 galactorrhea and, 31–32 hirsutism in, 210 hypogonadotropic hypogonadism and, 159 laboratory evaluation of, 32 prevalence of, 13t screening and assessment of, 13t treatment of, 32 Hypertension in diabetes mellitus, 282, 286 erectile dysfunction and, 226 hypokalemic, 113 in metabolic syndrome, 256, 259 obesity and, 242 paraneoplastic, 377t Hyperthyroidism cardiovascular complications of, 490, 508 definition of, 77 evaluation of, 80f in gestational trophoblastic disease, 223 hypercalcemia and, 423 lipoprotein disorders in, 331 paraneoplastic, 377t primary, 77t secondary, 77t thyrotoxicosis without, 77t Hyperthyroxinemia euthyroid, 67, 67t familial dysalbuminemic, 67, 67t Hypertrichosis, 210 Hypertriglyceridemia, familial, 326–327 Hyperuricemia metabolic syndrome and, 257 Hypoactive sexual desire, female, 231 Hypoalphalipoproteinemia, 330 Hypobetalipoproteinemia, familial, 328 Hypocalcemia, 429 chronic, 429–430 in chronic kidney disease, 433 classification of, 428t, 429–430 clinical features of, 405, 418, 499, 518 diagnosis of, 405 differential diagnosis of, 437 etiology of, 404–405, 404t, 429–430 genetic abnormalities and, 430–431 genetic patterns in, 435–436, 435f hyperphosphatemia and, 436 hypomagnesemia and, 432 hypoparathyroidism and, 418, 428t, 499, 518 See also Hypoparathyroidism osteoporosis associated with, 442 pancreatitis and, 429 pathophysiology of, 429–430 in PHP, 434–435 transient, 429 treatment of, 405, 418, 437–438 vitamin D deficiency and, 433–434 Hypoglycemia, 308 accidental, 315 approach to the patient, 315–316 in autoimmune insulin syndrome, 374 clinical features of, 310 in critical illness, 308t, 313 in diabetes mellitus autonomic failure associated with, 311–312, 311f defective glucose counterregulation and, 303, 311–312 impact and frequency of, 310, 513 prevention of, 312 risk factors for, 311, 312, 495, 513–514 unawareness of, 312 diagnosis of, 315, 495, 513 drug-induced, 308t, 313 endogenous hyperinsulinism and, 308t, 314–315 etiology of, 308, 308t factitious, 315 hormone action in, hormone deficiencies and, 308t, 313 with non–beta-cell tumors, 313–314 non-diabetic, 308r, 313–315 pathophysiology of, 310–312, 310t, 495, 513 recognition and documentation of, 315 recurrent, prevention of, 316 treatment of, 315–316 tumor-induced, 377t, 380 Hypogonadism cryptorchidism and, 159–160 erectile dysfunction in, 226 evaluation of, 163–164, 163f hypergonadotropic, 197 hypogonadotropic See Hypogonadotropic hypogonadism Klinefelter syndrome and, 159 obesity and, 242 testicular causes of, 159–161 Hypogonadotropic hypogonadism, 157 acquired, 158–159 amenorrhea in, 196–197 clinical features of, 46–47 congenital, 155t, 157–158, 187t diagnosis of, 47 etiology of, 187t hemochromatosis and, 159 hyperprolactinemia in, 159 isolated, 46, 196–197 obesity in, 159, 238 pathophysiology of, 157 sellar mass lesions and, 159 treatment of, 47 Hypokalemia in DKA, 275 in mineralocorticoid excess, 113 Hypomagnesemia, 394, 432 clinical features of, 395 etiology of, 394–395, 395t laboratory findings in, 394–395 treatment of, 395–396, 432 vitamin D deficiency and, 396 Hyponatremia, 58 in adrenal insufficiency, 121 clinical features of, 58 537 differential diagnosis of, 59t, 60 ECFV assessment and, 59, 59t etiology of, 58–59, 58t global considerations, 61 paraneoplastic, 376 pathophysiology of, 59–60 treatment of, 60–61 Hypoparathyroidism acquired, 431–432 chronic, 431 clinical features of, 430 etiology of, 404t genetic factors in, 430–431 hyperphosphatemia due to, 393, 393t hypocalcemia and, 404–405, 404t, 429–430 PTH absent, 428t, 430–432 PTH ineffective, 428t, 432–436, 435f PTH overwhelmed, 428t, 436–437 transient, 431–432 Hypophosphatasia, 459, 466–467 Hypophosphatemia, 390 chronic, 390–391 clinical features of, 391–392, 498 etiology of, 390–391, 390t, 498, 517 laboratory findings in, 391–392 mechanisms of, 389–390 osteomalacia and, 400 treatment of, 392, 392t, 517 Hypophysitis, 20, 196 Hypopituitarism, 18 acquired causes of, 18t, 20 cranial irradiation, 20 empty sella, 21, 489, 506 hypothalamic infiltration disorders, 20 inflammatory lesions, 20 lymphocytic hypophysitis, 20 pituitary apoplexy, 20–21 clinical features of, 21 developmental and genetic causes of, 18t developmental hypothalamic dysfunction, 19 pituitary dysplasia, 19 Prader-Willi syndrome See PraderWilli syndrome tissue-specific factor mutations, 19 diagnosis of, 21, 22t, 488, 506 treatment of, 21, 23t Hypospadias, isolated, 145 Hypothalamic disease glioma, 25 hamartoma, 25 hypopituitarism due to, 19, 20 See also Hypopituitarism metabolic effects of, 26 obesity in, 239–240, 244 Hypothalamic-pituitary-adrenal axis, 100, 102f, 487, 504 Hypothalamic-pituitary-gonadal axis, 195f Hypothalamic-pituitary-testis axis, 149–150, 149f Hypothalamic-pituitary vasculature, 17f Hypothalamus developmental dysfunction of, 19 in ovarian function regulation, 180–181, 181f vasculature of, 17f 538 Hypothyroidism, 62, 71 antithyroxine antibodies and, 374 autoimmune, 72 classification of, 72 clinical features of, 72t, 73–74, 74f laboratory evaluation of, 73–74, 490, 507 pathogenesis of, 72–73 prevalence of, 72 cardiovascular effects of, 490, 507 congenital, 63, 63t, 71–72 diagnosis of, 74–75, 75f differential diagnosis of, 75 diseases associated with, 75 etiology of, 71t, 75 evaluation of, 13t hirsutism in, 210 iatrogenic, 75 lipoprotein disorders in, 331 obesity in, 239, 244 overt, 72 pathogenesis of, 72–73 in pregnancy, 76, 88 prevalence of, 13t, 72 secondary, 75 subclinical, 72 treatment of, 76–77 Hypoventilation, in obesity, 242 Hysterectomy for endometrial cancer, 222 for ovarian cancer, 217 Ibandronate, for osteoporosis management/ prevention, 453f, 454 IBMPFD (inclusion body myopathy with Paget’s disease and frontotemporal dementia), 459 Ibuprofen, for dysmenorrhea, 199 Idiopathic growth hormone deficiency (IGHD), 36 Idiopathic hypercalcemia of infancy, 422–423 IDLs (intermediate-density lipoproteins), 317, 317f, 318t, 327t Ifosfamide, for testicular cancer, 177 IGF See Insulin-like growth factor (IGF) IMAGe syndrome, 119t Immune response/immune system, reference values, 474–481t Immunoglobulin(s), reference values, 478t Immunosuppressive therapy, adverse effects of, 445 Incidentaloma See Adrenal mass, incidentally discovered Incretins, for type diabetes mellitus, 298–300 Indomethacin, for nephrogenic diabetes insipidus, 56 Inferior petrosal venous sampling, in Cushing’s syndrome, 44–45, 111 Infertility, 187 after testicular cancer, 177 approach to the patient, 187–188 in CAH, 125 definition of, 187 etiology of, 187, 188f, 496, 514 evaluation of, 13t, 187–188, 496, 514 Index female, 187 hyperprolactinemia and, 31 male, 152, 188, 189 prevalence of, 13t, 187 psychological aspects of, 188 treatment of, 189–190 Inhibin, in male reproductive function, 152 Insulin action of, 266–267 adverse effects of, 244 biosynthesis of, 265 for DKA, 275 ectopic production of, 377t secretion of, 265, 266f, 270–271, 270f signal transduction pathway for, 2t, 266–267, 266f structure of, for type diabetes mellitus continuous subcutaneous infusion, 296–297, 296f multiple-component regimens, 296, 296f preparations, 294–295, 295t, 493, 512 twice-daily injections, 296, 296f for type diabetes mellitus, 299t, 301–302 Insulin aspart, 294–295, 295t Insulin-dependent diabetes mellitus (IDDM) See Diabetes mellitus, type Insulin detemir, 295, 295t, 493, 512 Insulin glargine, 295, 295t, 493, 512 Insulin glulisine, 294–295, 295t Insulin-like growth factor I (IGF-I) adverse effects of, 36 for GH-resistant syndromes, 36 secretion of, 35–36 signal transduction pathway for, 2t structure of, in thyroid hormone synthesis, 66 Insulin-like growth factor II (IGF-II), 377t, 380 Insulin-like growth factor II gene, 380 Insulin lispro, 294–295, 295t Insulinoma, 356 clinical features of, 344t, 356 definition of, 356 diagnosis of, 314–315, 356 endogenous hyperinsulinism due to, 314–315 epidemiology of, 314 incidence of, 314, 344t in MEN 1, 364f, 365 obesity in, 239 treatment of, 315, 356–357 Insulin resistance antibodies and, 373–374 autoimmune, 374 free fatty acids in, 255 lipoprotein disorders and, 331 in metabolic syndrome See Metabolic syndrome obesity and, 237, 241–242 pathophysiology of, 271 syndromes of, 271 treatment of, 260 Insulin resistance syndrome See Metabolic syndrome Insulin-resistant diabetes mellitus, 373–374 Insulin secretagogues adverse effects of, 300 properties of, 298–300, 300t for type diabetes mellitus, 298–300, 299t, 300t Insulin tolerance test, 102 Interferon-α (IFN-α), for carcinoid syndrome, 353 Intermediate-density lipoproteins (IDLs), 317, 317f, 318t, 327t Intrauterine devices (IUDs), 190t, 191 Intrauterine growth retardation, testicular disorders and, 145 In vitro fertilization (IVF), 189–190 Iodine deficiency of clinical features of, 66 global issues, 65, 65f, 489, 507 goiter and, 89 hypothyroidism and, 75 prevention of, 75 excess intake of, 75 metabolism and transport of, 64–65 recommended intake of, 66 Islet cell tumors, in MEN 1, 367 Isosexual precocity, 154 Itraconazole, drug interactions of, 229 “Ivory vertebra,” 462 Jansen’s disease, 419–420, 420f Jaw, osteonecrosis of, 454 Jod-Basedow effect, 87, 90 Juvenile goiter, 88 Juvenile Paget’s disease, 459 KAL gene, 19 Kallmann syndrome clinical features of, 19 etiology of, 19 genetic factors in, 19, 157 Kearns-Sayre syndrome clinical features of, 119t, 431 genetic factors in, 119t hypocalcemia and, 431 Kenney-Caffey syndrome, 430–431 Ketanserin, for diarrhea in carcinoid syndrome, 352 Ketoconazole adverse effects of, 46 for Cushing’s syndrome, 46, 111 drug interactions of, 229 for ectopic ACTH syndrome, 380 for hypercalcemia, 404 Ketoprofen, for dysmenorrhea, 199 Kidney cancer, paraneoplastic syndromes in, 377t Kidney disease/failure See Chronic kidney disease (CKD) Kinase inhibitors, for thyroid cancer, 97 Klinefelter syndrome, 138 clinical features of, 138–139, 140t, 159, 496, 515 genetic factors in, 159 Index gynecomastia in, 139, 159 hypogonadism due to, 159 pathophysiology of, 138 prevalence of, 13t screening and assessment of, 13t treatment of, 139 Krukenberg tumor, 215 Kussmaul respirations, 273 Kyphoplasty, 457 Lactate dehydrogenase, in testicular cancer, 173 Lactotrope, 16t, 23t Lamellar bone, 386 Lanreotide for acromegaly, 41–42 for carcinoid syndrome, 352–353 Laparoscopic adjustable silicon gastric banding, 251, 251f, 525 Laparoscopic adrenalectomy, 114, 114f Laron syndrome, 37 Laser therapy for hair removal, 213 Laurence-Moon-Biedl syndrome, 158, 240t LDL See Low-density lipoprotein (LDL) Lead poisoning, 484t Lecithin-cholesterol acyltransferase (LCAT), 320f deficiency of, 329–330 Leptin actions of, 236, 238f deficiency of, 19 genetics of, 237, 238t in hypogonadotropic hypogonadism, 197 mutations, hypopituitarism due to, 19 in obesity, 238t, 241 Leptin receptors, 237–238, 238t, 239f Leucovorin, for gestational trophoblastic disease, 223 Levonorgestrel in emergency contraception, 193 for hirsutism, 213 in oral contraceptives, 192 Levothyroxine adverse effects of, 76 for diffuse nontoxic goiter, 89 for hypothyroidism, 76–77 for subacute thyroiditis, 85 Leydig cell in androgen synthesis, 150 in testicular function regulation, 149–150, 149f LH See Luteinizing hormone (LH) Libido female, 230 male, 224, 228 Liddle’s syndrome, 115 Lifestyle modifications for metabolic syndrome, 258 for obesity, 247 Liothyronine, 76, 77 Lipid(s) dietary, transport of, 319–320, 320f hepatic, transport of, 320, 320f production of, 271 Lipid-modifying therapy See Lipoprotein disorders, treatment of Lipoatrophy diabetic, 288 in metabolic syndrome, 257 Lipodystrophy diabetes mellitus associated with, 307 in HIV infection, 254 lipoprotein disorders and, 331 metabolic syndrome and, 254 protease inhibitors and, 307 Lipohypertrophy, diabetic, 288 Lipoprotein(a) characteristics of, 318t, 320 elevated levels of, 325, 327t, 339 Lipoprotein(s) classification of, 317–319, 317f, 318t composition of, 317–319, 318t metabolism of endogenous pathway (hepatic lipids), 320, 320f exogenous pathway (dietary lipids), 319–320, 320f HDL and reverse cholesterol transport, 320–321, 320f proteins associated with, 318–319 Lipoprotein disorders, 321 in diabetes mellitus, 285–286 See also Metabolic syndrome diagnosis of, 332–333 with elevated HDL-C CETP deficiency, 330 familial hyperalphalipoproteinemia, 330 with elevated LDL–C and normal triglycerides, 321t, 322–325 autosomal dominant hypercholesterolemia due to mutations in PCSK9, 324 autosomal recessive hypercholesterolemia, 324 familial defective ApoB-100, 324 familial hypercholesterolemia, 322–324 polygenic hypercholesterolemia, 325 sitosterolemia, 324–325 with elevated lipoprotein(a), 325 with elevated triglycerides, 321t, 325–328 ApoA-V deficiency, 325–326 familial chylomicronemia syndrome, 325 familial combined hyperlipidemia, 327–328 familial dysbetalipoproteinemia, 326 familial hypertriglyceridemia, 326–327 GPIHBP1 deficiency, 326 hepatic lipase deficiency, 326 in metabolic syndrome, 256, 259 erectile dysfunction in, 226 Frederickson classification of, 321–322, 321t with low ApoB familial hypobetalipoproteinemia, 328 PCSK9 deficiency, 328 with low HDL-C genetic deficiency of apoA-I, 329 LCAT deficiency, 329–330 primary hypoalphalipoproteinemia, 330 Tangier disease, 329 prevalence of, 13t 539 screening for classification of results, 485t recommendations, 13t, 332 secondary forms, 327t alcohol consumption and, 331–332 in Cushing’s syndrome, 332 diabetes mellitus and, 331 drug-related, 327t, 332 estrogen and, 332 liver disorders and, 331 lysosomal storage diseases and, 332 in obesity, 330 renal disorders and, 331, 502, 523 thyroid disease and, 331 treatment of, 334 bile acid sequestrants, 336–337, 337t for CHD risk reduction, 333–334 cholesterol absorption inhibitors, 336, 337t clinical approach to, 334–336 combination drug therapy, 338–339 dietary modification, 335 elevated lipoprotein(a) management, 339 fibric acid derivatives, 337t, 338 foods and dietary additives, 335 LDL apheresis, 339 lifestyle modifications, 335 low HDL–C management, 339 in metabolic syndrome, 259 nicotinic acid, 337–338, 337t omega-3 fatty acids, 337t, 338 statins, 336, 337t Lipoprotein lipase (LPL), 255, 319 Lipoprotein lipase (LPL) deficiency, 322t, 325 Liraglutide, for diabetes mellitus, 299t, 300, 300t Lithium, adverse effects of erectile dysfunction, 227t hypercalcemia, 418–419 obesity, 244 Liver disease/failure lipoprotein disorders in, 331 obesity and, 242 Liver transplantation, for metastatic NETs, 362 Locaserin, 251 Loop diuretics for hypercalcemia of malignancy, 378 Looser’s zones, 400 Lovastatin adverse effects of, 337t for hyperlipidemia, 337t Low-carbohydrate diet, 247 Low-density lipoprotein (LDL) composition of, 317, 317f elevated disorders associated with, 322t, 325–328 secondary causes of, 327t, 502, 522 estimation of, 332 goal for, in diabetes mellitus, 258–259, 286 lowering levels of See Lipoprotein disorders, treatment of in metabolic syndrome, 256 Low-density lipoprotein (LDL) apheresis, 339 540 LPL (lipoprotein lipase), 255, 319 deficiency of, 325 Lung cancer, paraneoplastic syndromes in, 375–376, 377t Lung disease, obesity and, 242 Luteinizing hormone (LH), 46 action of, 4, 46 deficiency of, 23t ectopic production of, 377t laboratory evaluation of, 22t during neonatal period, 181, 181f reference values, 479t secretion of, 46 synthesis of, 46 Luteinizing hormone (LH) receptor, disorders of, 142, 143t Lymphocytic hypophysitis, 20 Lymphoid malignancies paraneoplastic syndromes in, 376, 377t in thyroid, 98 Lynch syndrome See Hereditary nonpolyposis colon cancer Lysosomal storage diseases, lipoprotein disorders in, 332 Maffucci syndrome, 218, 469 Magnesium deficiency of, 418 metabolism of, 394 for osteoporosis management/prevention, 450 Magnesium sulfate, for eclampsia in pregnancy, 498, 517 Magnesium-wasting syndrome, 394, 395t Magnetic resonance imaging (MRI) in adrenocortical carcinoma, 118f in CAH, 126f in Cushing’s syndrome, 110, 110f in pancreatic endocrine tumors, 360–361 in pituitary tumors, 27, 27f Male feminization, paraneoplastic, 377t Male pseudohermaphroditism, 142 Male reproductive disorders, 152 in adulthood, 157 androgen insensitivity syndromes See Androgen insensitivity syndrome (AIS) gynecomastia See Gynecomastia hypogonadism See Hypogonadism hypogonadotropic hypogonadism See Hypogonadotropic hypogonadism aging-related, 162 approach to the patient, 163–164, 164f pathophysiology of, 162–163 treatment of gonadotropins for, 164 testosterone for See Testosterone therapy evaluation of gonadotropin and inhibin measurements, 152 history and physical examination, 152 semen analysis, 153 testicular biopsy, 153 testosterone assays, 153 infertility, 152, 189 Malignant pheochromocytoma, 130 Malignant transformation, 177 Index Malnutrition, gonadotropin deficiency due to, 158 MAOIs See Monoamine oxidase inhibitors (MAOIs) Marble bone disease, 464 Marijuana use/abuse, 227t “Master gland,” 16 Maturity-onset diabetes of the young (MODY), 262, 262t clinical features of, 271–272 genetic factors in, 271–272 Mayer-Rokitansky-Kuster-Hauser syndrome, 147, 195 Mazindol, for weight loss, 250 McCune-Albright syndrome clinical features of, 24, 107, 155, 467 Cushing’s syndrome in, 107 genetic factors in, 107, 154–155, 420f, 467 laboratory findings in, 468 pituitary tumors in, 24 radiographic findings in, 467–468, 468f treatment of, 468 Mediastinal nonseminoma, 177 Medroxyprogesterone for contraception, 192 for menorrhagia, 201 for polycystic ovarian syndrome, 197 Mefenamic acid for dysmenorrhea, 199 for menorrhagia, 201 Megalin, Meige’s disease/syndrome, 218 Melanin-concentrating hormone, 236 MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome, 431 Melorheostosis, 465–466 Membrane receptor(s), 5–6, 5f Membrane receptor families, 2–3, 2t MEN1 gene See Multiple endocrine neoplasia type (MEN 1) Menarche, age at, 185, 185t, 194 Meningioma, sellar, 25 Menopause, 200 hirsutism after, 212 ovarian function during, 443–444 from perimenopause to, 201 screening and assessment of, 13t symptom relief in, 202 Menorrhagia, 201 Menstrual cycle duration of, 8, follicular phase of, 183–184, 184f hormonal integration of, 183, 183f luteal phase of, 184 relationships between gonadotropins, follicle development, gonadal secretion, and endometrial changes during, 183, 183f Menstrual disorders, 194 definition of, 194 diagnosis of, 195, 196f dysmenorrhea, 199 epidemiology of, 194 obesity and, 242 MEN syndromes See Multiple endocrine neoplasia (MEN) syndromes Mercury exposure/poisoning, 484t Mesenchymal tumor, paraneoplastic syndromes in, 377t Metabolic syndrome, 253 adiponectin in, 257 age and, 254 cardiovascular disease and, 254, 257 clinical features of, 257 cytokines in, 256–257 diabetes mellitus and, 254, 257, 260, 271 diagnosis of, 253t, 258 dyslipidemia in, 256 epidemiology of, 253–254, 254f fatty liver disease and, 257 glucose intolerance in, 256 hypertension in, 256, 259 hyperuricemia/uric acid stones in, 257 insulin resistance in, 255–256, 260 lipodystrophy and, 254 obesity and, 258 pathophysiology of, 255–257, 255f polycystic ovary syndrome and, 257 risk factors for, 255 sedentary lifestyle and, 254 sleep apnea and, 257 treatment of, 258–260 waist circumference and, 256 Metastatic calcification, 469, 469t Metformin for metabolic syndrome, 260 for polycystic ovarian syndrome, 197 for prediabetes, 271 for type diabetes mellitus, 298, 299t, 302, 493, 512 MET gene, in thyroid cancer, 94t Methimazole adverse effects of, 82 for Graves’ disease, 81 Methotrexate for ectopic pregnancy, 198 erectile dysfunction, 227t for gestational trophoblastic disease, 223 therapeutic monitoring of, 483t Methylprednisolone, for Graves, ophthalmopathy, 83 Metoclopramide, for gastrointestinal dysfunction in diabetes mellitus, 284 Metyrapone for Cushing’s syndrome, 46, 111 for ectopic ACTH syndrome, 380 Mibefradil, drug interactions of, 229 Microalbuminuria, in diabetic nephropathy, 281–282, 281f Midline carcinoma of uncertain histogenesis, 177 Miglitol, for diabetes mellitus, 299t, 300 Milk-alkali syndrome, 403, 424–425 Mineral(s), reference ranges for, 484t Mineralization, defective, 466–467 Mineralocorticoid(s) actions of, 100 for adrenal insufficiency, 123f, 124 production of, 101f, 102–103, 102f Mineralocorticoid excess, 111 clinical features of, 113 diagnosis of, 113, 114f, 115t differential diagnosis of, 113–115, 114f Index epidemiology of, 111 etiology of, 111–113, 112t, 487, 504 treatment of, 114, 114f Minoxidil, adverse effects of, 210 Mirtazapine, adverse effects of, 244 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome, 431 Mitochondrial uncoupling protein, 236 Mitotane, for Cushing’s syndrome, 46, 111 Mitotane, for ectopic ACTH syndrome, 380 Mittelschmerz, 184, 198 Mixed gonadal dysgenesis, 140t, 141 MODY See Maturity-onset diabetes of the young (MODY) Monoamine oxidase inhibitors (MAOIs), adverse effects of erectile dysfunction, 227t obesity, 244 Mononeuropathy, diabetic, 282–283 MRI See Magnetic resonance imaging (MRI) MSH See α-Melanocyte-stimulating hormone (MSH) Müllerian agenesis, 147, 195–196 Müllerian epithelium, 215 Müllerian inhibiting substance, 218 Multiple endocrine neoplasia (MEN) syndromes definition of, 363 mixed syndromes, 363t See also Carney syndrome; Neurofibromatosis type (NF1); von Hippel-Lindau disease type See Multiple endocrine neoplasia type (MEN 1) type See Multiple endocrine neoplasia type (MEN 2) Multiple endocrine neoplasia type (MEN 1), 363 adrenal cortical tumors in, 366 age at onset of endocrine tumor expression in, 364, 364f carcinoid tumors in, 347t, 366 clinical features of, 24t, 363t, 364–366, 364f, 497, 516–517 diseases associated with, 363t enteropancreatic tumors in, 364 epidemiology of, 364 gastrinomas in, 364, 364f genetic factors in, 132, 347t, 364–365, 366, 366f, 413, 413f glucagonomas in, 365 hyperparathyroidism in, 364, 366–367, 412 insulinomas in, 364f, 365 pancreatic tumors in, 347t, 365, 367 pathogenesis of, 10–11 pheochromocytoma in, 132f pituitary tumors in, 24, 24t, 357–366, 363t, 367 prevalence of, 364 treatment of, 366–367 unusual manifestations of, 366 Verner-Morrison (watery diarrhea) syndrome in, 365 ZES and, 355–356 Multiple endocrine neoplasia type (MEN 2), 367 clinical features of, 363t, 367–368 diseases associated with, 363t genetic factors in, 132, 368–369, 369f hyperparathyroidism in, 371 medullary thyroid carcinoma in, 130, 132f, 370–371 pathogenesis of, 11 pheochromocytoma in, 371 screening for, 369–370 treatment of, 370–371 type 2A clinical features of, 363t, 368, 412 genetic factors in, 368, 369f hyperparathyroidism in, 412 pheochromocytoma in, 130, 132, 368, 371 screening for, 369–370 type 2B clinical features of, 363t, 368, 412 genetic factors in, 368–369, 369f hyperparathyroidism in, 412 pheochromocytoma in, 130 screening for, 369–370 Multiple exostosis, 469 Multiple myeloma hypercalcemia in, 376 hyperlipidemia in, 502, 523 paraneoplastic syndromes in, 376 Multiple sclerosis (MS), erectile dysfunction in, 226 Mumps, orchitis in, 160 Myocardial infarction (MI), erectile dysfunction and, 228 Myositis ossificans, 470 Myositis ossificans progressiva, 470 MyPyramid food guide, 247 Myxedema characteristics of, 73 in hypothyroidism, 73, 239 Myxedema coma, 77, 490, 508 NAFLD See Nonalcoholic fatty liver disease (NAFLD) Naltrexone, 251 Naproxen, for dysmenorrhea, 199 Nateglinide, for diabetes mellitus, 298, 300t Necrobiosis lipoidica diabeticorum, 288 Nelson’s syndrome, 46 Neonate(s) diabetes in, 272 FSH levels in, 181, 181f LH levels in, 181, 181f Neuroendocrine tumors (NETs) See also Carcinoid tumors biology of, 342–348, 343t classification of, 342–348, 343t gastrinomas See Gastrinoma gastrointestinal, 342, 343t genetic syndromes associated with, 347–348, 347t metastatic, 361–362 pancreatic See Pancreatic endocrine tumors pathology of, 342–348, 343t 541 prognostic factors in, 346t treatment of, 61f, 361–362 well-differentiated, 346 Neurofibromatosis type (NF1) carcinoid tumors in, 347t, 348 clinical features of, 130, 131f genetic factors in, 132, 347t, 348, 371 pheochromocytoma in, 130, 131f skin manifestations of, 130, 131f Neurohypophysis disorders of adipsic hypernatremia See Adipsic hypernatremia diabetes insipidus See Diabetes insipidus (DI) hormones produced by oxytocin, 50f, 52 vasopressin See Arginine vasopressin (AVP) Neuroleptics, adverse effects of, 226 Neurologic disease, testicular dysfunction due to, 161 Neuropeptide Y, 236 NF1 See Neurofibromatosis type (NF1) NF1 gene, 130, 132, 134f, 371 Nicotinic acid adverse effects of, 337t, 338 for lipoprotein disorders, 259, 337–338, 337t Nimesulide, for dysmenorrhea, 199 NIS gene, 64 Nitrates, interaction with phosphodiesterase type inhibitors, 229 Nitric oxide in clitoral engorgement, 231 in erection, 224, 225f Nitroprusside, therapeutic monitoring of, 483t Nonalcoholic fatty liver disease (NAFLD) in metabolic syndrome, 257 obesity and, 242 Nonexercise activity thermogenesis, 241 Non–insulin-dependent diabetes mellitus (NIDDM) See Diabetes mellitus, type Nonseminoma, mediastinal, 177 Nonsteroidal anti-inflammatory drugs (NSAIDs), for dysmenorrhea, 199 Norethindrone acetate, in perimenopause, 201 Norgestimate, for hirsutism, 213 Norgestrel, for hirsutism, 213 Normal saline, for SIAD, 379 NO SPECS mnemonic, in Graves’ disease, 79 Nuclear receptor(s), 6–7, 7f hormone action through, signaling, 6, 7f Nuclear thyroid hormone receptors, 68–69, 68f Nutritional short stature, 37 Nutritional support/therapy for diabetes mellitus, 291–292, 291t for lipoprotein disorders, 335 for metabolic syndrome, 258 for obesity, 247–249, 248f, 248t 542 Obesity bone and joint disorders and, 243, 246t cancer and, 243 cardiovascular disease and, 242, 246t central adiposity in, 254 comorbid conditions, 246–247, 246t contraceptive methods and, 193 definition of, 234 diabetes mellitus and, 241–242, 246t drug-induced, 244 erectile dysfunction in, 226 etiology of, 237–239 craniopharyngioma in, 239–240 Cushing’s syndrome in, 239 energy expenditure in, 241 food intake in, 241 genetic syndromes, 237–239, 238t, 240t, 503, 524 genetic vs environmental factors in, 237 hypogonadotropic hypogonadism in, 159 hypothalamic disorders in, 26, 239–240 hypothyroidism in, 239 insulinoma in, 239 leptin in, 239f, 241 evaluation of, 234, 244 gallstones and, 243 gastrointestinal disorders and, 246t genitourinary disorders and, 246t history focused on, 244 hypertension and, 242, 246t lipoprotein disorders in, 330 liver disease and, 242–243 in metabolic syndrome, 253t, 254, 258 neurologic disorders and, 246t physical fitness and, 246 prevalence of, 13t, 234–235 reproductive disorders and, 189, 242 respiratory disorders and, 242, 246t screening and assessment of, 13t skin manifestations of, 243, 246t sleep apnea and, 242 treatment of, 247, 503, 524–525 bariatric surgery, 251–252, 251f, 525 behavioral therapy, 249 diet therapy, 247–249 exercise program, 249 goal of, 247 lifestyle management, 247 patient’s readiness to change and, 247 pharmacotherapy, 249–251 selection of, 248f, 248t Obesity hypoventilation syndrome, 242 ob gene, 237, 536 Obstructive sleep apnea in metabolic syndrome, 257 obesity and, 242 Octreotide for acromegaly, 41–42 for carcinoid syndrome, 352–353 for diabetic diarrhea, 284 for glucagonoma, 357 for oncogenic osteomalacia, 381 for VIPoma, 358 Oligomenorrhea, 145, 194 See also Amenorrhea Ollier’s disease, 218, 469 Index Omega-3 fatty acids adverse effects of, 337t for lipoprotein disorders, 259, 337t, 338 Omentectomy, in ovarian cancer, 217 Oncogene(s), in thyroid cancer, 93–95, 94t Oogonia, 178, 179f Oophorectomy, for ovarian germ cell tumors, 219 Ophthalmopathy, Graves’, 79–80, 79f, 83, 491, 508 Optic gliomas, 25 Oral contraceptives, 191 adverse effects of, 192, 192t for amenorrhea, 197 characteristics of, 191–192 contraindications to, 192, 192t, 213 for dysmenorrhea, 199 for hirsutism, 213 in perimenopause, 201 for polycystic ovarian syndrome, 197 Orchiectomy, for testicular cancer, 173, 175 Orchitis, viral, 160 Orgasm female orgasmic disorder, 231 Orlistat, 250, 258 Osmoreceptors, 50 Osmoregulation, 50–51, 57f Ossification ectopic, 469t, 470 extraskeletal, 71t, 469–470 Osteitis fibrosa cystica, 414–415, 437 Osteoarthritis, obesity and, 243 Osteoblast(s), 384, 385f, 387f, 460 Osteoblastoma, 377t Osteochondrodysplasias, 468–469 Osteochondromatosis, 469 Osteoclast(s), 385f, 386, 387f, 460 Osteocyte(s), 384 Osteodystrophy, renal, 424 Osteomalacia axial, 467 diagnosis of, 400 hypophosphatemia and, 400 oncogenic (tumor-induced), 377t, 381 secondary hyperparathyroidism and, 424 vitamin D deficiency and, 400 Osteomyelitis, treatment of, 287 Osteonecrosis of the jaw, 454 Osteopenia, 440f Osteopetrosis clinical features of, 464 etiology of, 464 genetic factors in, 464 laboratory findings in, 464 radiography of, 464 treatment of, 464–465 types of, 464 Osteopoikilosis, 466 Osteoporosis, 439 approach to the patient, 446–447, 447t biochemical markers in, 447, 447t bone biopsy in, 447 bone mass measurement in, 445–446, 445f, 446t, 520 definition of, 439, 501, 521 diseases associated with, 444, 444t, 500, 520 epidemiology of, 13t, 439, 500, 520 fractures associated with See also specific fractures and sites epidemiology of, 439–440, 439f, 500, 520 prevention of osteoporosis management/ prevention for, 447–448, 521 postmenopausal hormone therapy in, 202, 203t, 450–451, 451f risk factors for, 439f, 440, 440t, 500, 520 glucocorticoid-induced, 457–458 laboratory evaluation of, 446–447, 500, 520 pathophysiology of, 441 bone remodeling in, 441–442, 441f calcium nutrition in, 443 chronic disease in, 444, 444t cigarette smoking in, 445 estrogen status in, 443–444, 443f medications in, 444–445, 444t physical activity in, 444 vitamin D deficiency in, 442–443 prevention of, 202, 203t screening for, 13t, 500, 520–521 treatment of, 447, 501, 521 bisphosphonates, 452–454, 453f calcitonin, 454–455 calcium supplementation, 448–450, 449t denosumab, 455, 455f estrogens, 450–451, 451f exercise, 450 fluoride, 452-453 fracture management, 447–448 GH, 457 magnesium, 450 monitoring of, 457 nonpharmacologic, 457 nutritional recommendations, 448–450, 449t progestins, 452 PTH, 455–456, 456f risk factor reduction, 448, 449f SERMs, 452, 454f strontium ranelate, 457 vitamin D, 450 vitamin K, 450 Osteoprotegerin, 442, 443f Osteosclerosis, 466 Ovarian cancer, 215 breast/ovarian cancer syndrome, 216 clinical features of, 216 epidemiology of, 215 epithelial, 215–216 etiology of, 15 genetic factors in, 216 germ cell tumors, 218–219 incidence of, 215 paraneoplastic syndromes in, 377t pathology of, 215 postmenopausal hormone therapy and, 204t, 206 prognosis of, 217t, 218 protective factors for, 215 recurrent, 217–218 risk factors for, 215 Index screening for, 216 sex cord tumors, 218 staging of, 216, 217t treatment of, 217–218 tumor markers in, 216 Ovarian cyst, treatment of, 198 Ovarian failure, primary, 196–197 Ovarian follicles, 179–180, 180f Ovarian function clinical assessment of, 184 regulation of, 181 hypothalamic secretion in, 180–181, 181f ovarian peptides in, 182–183 ovarian steroids in, 181–182, 182f pituitary secretion in, 180–181, 181f Ovarian insufficiency, primary, 196–197 Ovarian peptides, 182–183 Ovarian reserve, 188 Ovarian steroids, 181–182, 182f See also Estrogen(s) Ovarian torsion, 198 Ovary See also Ovarian cancer development of, 178, 179f, 180f estrogen production in, 181–182, 182f metastatic disease to, 217 sex cord tumors of, 218 teratoma of, 218–219 Overfeeding, 235 Overweight, 234, 246t Ovotesticular disorders of sexual development, 140t, 141 Ovulation, 496, 514 Ovulatory dysfunction, 189, 196–197 Oxidative stress hypothesis, 255–256 Oxytocin, 50f, 52 p16 gene, in thyroid cancer, 94t p21/WAF gene, in thyroid cancer, 94t p53 gene, in thyroid cancer, 94t Pachydermoperiostosis, 468 Paclitaxel for ovarian cancer, 217 for testicular cancer, 177 Paget’s disease of bone, 459 cardiovascular disease and, 461 clinical features of, 460–461, 521–522 complications of, 461 diagnosis of, 461–462, 461f, 462f, 501, 521–522 diseases associated with, 461 epidemiology of, 459 etiology of, 459–460, 460f fractures and, 461 genetic factors in, 459–460 juvenile, 459 pathophysiology of, 460f treatment of, 462–464, 463t, 501–502, 522 Painless thyroiditis, 85–86 Pallister-Hall syndrome, 25 Pamidronate for hypercalcemia, 378, 404, 427t, 428 for Paget’s disease of bone, 463, 463t Pancreatic cancer, paraneoplastic syndromes in, 377t Pancreatic endocrine tumors, 354 See also Gastrinoma; VIPomas (vasoactive intestinal peptidomas) classification of, 343, 344–345t, 346 clinical features of, 344–345t, 354 Cushing’s syndrome and, 359–360 general characteristics of, 343t genetic syndromes associated with, 347–348, 347t glucagonoma See Glucagonoma GRFomas, 359 insulinoma See Insulinoma localization of, 360–361 in MEN 1, 365, 367 misnomer of, 346 nonfunctional, 359 clinical features of, 359 definition of, 359 diagnosis of, 359 treatment of, 359 paraneoplastic syndromes in, 377t prevalence of, 344–345t, 346–347 prognostic factors in, 346t rare syndromes, 359–360 somatostatinoma See Somatostatinoma treatment of, 354, 362 Pancreatitis, hypocalcemia in, 405, 429 Pap smear, for cervical cancer screening, 220 Parachlorophenylanine, for carcinoid syndrome, 353–354 Paracrine regulation, Paraganglial system, 127, 128f Paraganglioma definition of, 127 genetic screening for, 132, 134, 134f imaging in, 133f pheochromocytoma and, 131, 133f topographic sites, 127, 128f Paraneoplastic syndromes definition of, 375 endocrinologic, 375, 377t Parathyroid disease, 406 hypercalcemia in, 402–403 Parathyroidectomy, 366–367, 417–418, 437, 499, 518 Parathyroid hormone (PTH), 406 actions of, 400, 402, 402f, 406–407, 456, 456f, 499, 519–520 assessment of, 10 in calcium metabolism, 8, 420f deficiency of, 404–405 ectopic production of, 375, 377t, 404, 524, 526 excess of, 402–403 in hypercalcemia, 425–426 immunoreactive, in primary hyperparathyroidism, 416, 416f metabolism of, 408 in osteoporosis management/prevention, 455–456, 456f physiology of, 400 PTHrP action and, 409–410, 410f secretion of, 407–408 signal transduction pathway for, 2t, structure of, 400, 407, 409f synthesis of, 407 543 Parathyroid hormone (PTH)/PTHrP receptor, 409, 409f Parathyroid hormone–related peptide (PTHrP), Parathyroid hormone–related protein (PTHrP), 408 actions of, 409–410, 410f ectopic production of, 376, 377t PTH and, 409–410, 409f structure of, 408–409, 409f Parathyroid hormone (PTH) resistance, 435, 435f Parental disomy, 222 Parenteral nutrition diabetes mellitus management and, 306 hypercalcemia in, 403 Paroxetine, adverse effects of, 244 PAX-8, 63, 63t PCOS See Polycystic ovarian syndrome (PCOS) PCSK9 deficiency, 328 PCSK9 mutations, 322t, 324, 328 Pedometer, 249 Pegvisomant, for acromegaly, 42, 367 Pelvic inflammatory disease (PID), 198, 198t Pelvic pain acute, 198, 198t in cervical cancer, 220 chronic, 198 Pemberton’s sign, 89 Pendred syndrome, 65 Pendrin, 63t, 65 Penile tumescence, 224 Peptide(s), ovarian, 182–183 Peptide YY, 236 Perimenopause, 200 clinical features of, 200–201 definition of, 200 diagnosis of, 200 physiology of, 200, 201f transition to menopause, 201 treatment of, 201 Periodic hypothermia syndrome, 26 Peritoneal dialysis for hypercalcemia, 429 Peroxisome proliferator-activated receptor(s), 236 Persistent müllerian duct syndrome, 145 Peutz-Jeghers syndrome, 218 P450 oxidoreductase deficiency, 125t PGA syndromes See Polyglandular autoimmune (PGA) syndromes Phendimetrazine, for weight loss, 250 Phenothiazines, adverse effects of, 227t Phenotypic sex definition of, 138 disorders of, 141 Phenoxybenzamine, for pheochromocytoma, 129 Phentermine for metabolic syndrome, 258 for weight loss, 250, 251 Phenytoin adverse effects of, 210 therapeutic monitoring of, 483t Pheochromocytoma, 127 biochemical testing in, 129t clinical features of, 127–128, 128t 544 Pheochromocytoma (Cont.): definition of, 127 diagnosis of, 128, 129t biochemical testing in, 128–129 imaging in, 129 differential diagnosis of, 129, 492, 510 epidemiology of, 127 etiology of, 127 genetic screening for, 132, 134, 134f imaging in, 129t malignant, 130 in MEN syndromes, 130, 132f, 368, 371 in neurofibromatosis, 130, 131f in paraganglioma syndrome, 131, 133f paraneoplastic syndromes in, 379 pathogenesis of, 127, 128f during pregnancy, 130 topographic sites, 127, 128f treatment of, 129–130, 492, 510 in von Hippel-Lindau syndrome, 131, 132–134, 133f See also von Hippel-Lindau disease PHEX gene, 381 Phosphate/phosphorus definition of, 389 for hypercalcemia, 378, 427t, 429 metabolism of, 389 Phosphatonin, ectopic production of, 377t, 381 Phosphodiesterase type inhibitors action of, 224, 225f adverse effects of, 228–229 for erectile dysfunction, 228–229 for female sexual dysfunction, 232 interaction with nitrates, 229 Phospholipid transfer protein (PLTP), 321 PHP See Pseudohypoparathyroidism (PHP) Physical activity, energy required for, 236 PID (pelvic inflammatory disease), 198, 198t Pigmented pretibial papules, in diabetes mellitus, 288 Pilosebaceous unit, 209 Pioglitazone, for diabetes mellitus, 299t, 301 PIT-1, 19, 63t Pituitary apoplexy, 20–21, 120t Pituitary axes, 17f Pituitary disorders anterior insufficiency See Hypopituitarism tumors See Pituitary tumors (adenomas) posterior adipsic hypernatremia See Adipsic hypernatremia diabetes insipidus See Diabetes insipidus (DI) Pituitary gland anatomy of, 17–18, 17f anterior See Anterior pituitary basic fibroblast growth factor in, 24 development of, 16t, 18 hormones produced by, 16–17, 16f, 487, 504–505 insufficiency of See Hypopituitarism laboratory evaluation of, 22t posterior See Neurohypophysis Index Pituitary hormones expression and regulation of, 6t in ovarian function regulation, 180–181, 181f secretion of, 17f Pituitary tumors (adenomas), 21 ACTH-secreting, 44, 45t See also Cushing’s syndrome in Carney syndrome, 24, 24t classification of, 21, 23t diagnosis of, 26 histologic evaluation in, 28 laboratory studies in, 27–28, 28t, 488, 505 local mass effects, 26–27, 26t MRI in, 27, 27f ophthalmologic evaluation in, 27 in familial acromegaly, 24, 24t gonadotropin-producing, 47–48 hormone-excess syndromes due to, 17 local mass effects of, 26–27, 26t in McCune-Albright syndrome, 24 in MEN 1, 24, 24t, 363t, 365–366, 367 metabolic effects of, 26 metastatic, 25 nonfunctioning, 47–48, 48f pathogenesis of, 23–24 prevalence of, 21 secondary adrenal insufficiency and, 120–121, 120t sellar mass lesions, 25–26, 26t, 159 treatment of medical, 30, 488, 505 radiation therapy, 29–30 surgical, 28–29, 29f TSH–secreting, 49 thyrotoxicosis due to, 84 Platelet(s), reference values for, 473t Platybasia, 461 Plicamycin, for hypercalcemia, 428 PLTP (phospholipid transfer protein), 321 Pneumocystis pneumonia (PcP), ectopic ACTH production and, 380 POEMS syndrome (Crow-Fukase syndrome), 374 Poisoning/drug overdose, 482–484t Polycystic ovarian syndrome (PCOS) in CAH, 146–147 hirsutism in, 209, 212 infertility in, 188 insulin resistance in, 271 menstrual disorders in, 197 in metabolic syndrome, 257 obesity and, 242 prevalence of, 13t screening and assessment of, 13t treatment of, 197 Polydipsia iatrogenic, 54, 56 primary, 53, 56 psychogenic, 53–54, 56 Polygenic hypercholesterolemia, 325 Polyglandular autoimmune (PGA) syndromes clinical features of, 372–373, 372t diagnosis of, 373 multiple endocrine organ effects of, 372, 372t testicular dysfunction due to, 160 treatment of, 373 type I, 372, 372t, 431 type II, 372–373, 372t Polyneuropathy, diabetic, 282–283 POMC See Proopiomelanocortin (POMC) POMC gene, 120t Postcoital contraception, 192–193 Postmenopausal hormone therapy, 201 approach to the patient, 206–208, 207f benefits of, 202, 203t candidates for, 206, 207f discontinuation of, health status changes following, 206 endometrial cancer and, 21 for osteoporotic fracture prevention, 451–452, 451f probable or uncertain risks and benefits of, 203–204t, 205–206 risks associated with, 202–206, 203t, 496, 515 Postpartum period, thyroiditis in, 86 PPHP (pseudopseudohypoparathyroidism), 434, 434t PPNAD (primary pigmented nodular adrenal disease), 107 PRAD 1, 413f, 414 Prader-Willi syndrome clinical features of, 20, 158, 239, 240t, 524 genetic factors in, 19–20, 158, 239 hypopituitarism due to, 19–20 obesity in, 239, 240t Pramlintide, for diabetes mellitus, 297, 299t Pravastatin, for hyperlipidemia, 337t Precocious puberty female, 185–186, 186t male approach to the patient, 156 central, 154 etiology of, 154t, 155t familial male-limited, 154 gonadotropin-dependent, 154 gonadotropin-independent, 154–155 treatment of, 156 ovarian germ cell tumors and, 218–219 Precocity heterosexual, 154, 155–156, 186 isosexual, 154 Prednisone for ACTH deficiency, 43 for CAH, 213 for Graves’ ophthalmopathy, 83 for hypercalcemia, 404 for hypercalcemia of malignancy, 378 for subacute thyroiditis, 85 Preeclampsia, in gestational trophoblastic disease, 223 Pregabalin, for diabetic neuropathy, 293 Pregnancy eclampsia in, 498, 517 Graves’ disease in, 83 hypothyroidism in, 76 pheochromocytoma in, 130 prolactinoma in, 34 thyroid function during, 88 Pregnenolone, 101f, 104 Index Prehypertension, 259 Premature ejaculation, 225 Premature menopause See Primary ovarian insufficiency Premature ovarian failure See Primary ovarian insufficiency Priapism, 225 Primary ovarian insufficiency, 197 Primary pigmented nodular adrenal disease (PPNAD), 107 Primary polydipsia, 53, 56 Progesterone actions of, 182 adverse effects of, 227t Progestins in oral contraceptives, 192 in osteoporosis management/prevention, 452 in perimenopause, 201 for polycystic ovarian syndrome, 197 Progressive diaphyseal dysplasia, 465 Prohormone convertase 1, 238t Prolactin, 30 action of, 30 laboratory evaluation of, 22t secretion of, 30 synthesis of, 30 Prolactinoma, 32 clinical features of, 32 diagnosis of, 32–33 etiology of, 32 during pregnancy, 34 prevalence of, 32 screening tests for, 28t treatment of, 33–34, 33f Prometrium, for polycystic ovarian syndrome, 197 Proopiomelanocortin (POMC) deficiency, 120t ectopic ATCH production and, 379 in obesity, 238, 238t, 239f PROP-1, 19, 63t, 120t Propranolol for Graves’ disease, 82 for pheochromocytoma, 129 Propylthiouracil, for Graves’ disease, 81 Prostaglandin(s), in dysmenorrhea, 199 Prostaglandin E2, ectopic production of, 377t Prostate cancer erectile dysfunction after treatment of, 226 paraneoplastic syndromes in, 377t testosterone therapy and, 170 Prostate-specific antigen (PSA) reference values, 480t testosterone therapy and, 170 Protein(s) lipoprotein-associated, 318–319 PTH-related, 408 serum binding, 66–67 thyroid hormone binding, 67 Protein C, reference values, 473t Protein G, 5f, Protein kinase A, 103 Protein kinase C, 278 Protein S, reference values, 473t Pseudohermaphroditism female See 46,XX disorders male See 44,XY disorders Pseudohypoparathyroidism (PHP) classification of, 434–435, 434t genetic factors in, 420f, 435–436, 435f hypocalcemia and, 434 treatment of, 436 types of, 435 Pseudopseudohypoparathyroidism (PPHP), 434, 434t Pseudotumor cerebri, 76 Psychogenic polydipsia, 53, 56 Psychosocial issues, in diabetes mellitus, 304–305 Psychosocial short stature, 37 Psyllium mucilloid, with orlistat, 250 PTH See Parathyroid hormone (PTH) PTH-related peptide, 402 Puberty definition of, 148 delayed female, 186–187, 186t, 187t male, 154t, 156–157 normal development during female, 185, 185t male, 148–149, 149f precocious female, 185–186, 186t male See Precocious puberty, male stages of, 149, 149f Pyknodysostosis, 465 Pyridoxine (vitamin B6), reference range for, 484t QT interval, prolonged, 405, 518 Rachitic rosary, 400 Radiation therapy for acromegaly, 42 adverse effects of pituitary, 20, 29–30, 120t testicular dysfunction, 160 thyroid cancer, 92, 93 for pituitary tumors, 29 for testicular cancer, 175 Radiofrequency ablation, for neuroendocrine tumor liver metastases, 362 Radiography in fibrous dysplasia, 467–468, 468f in McCune-Albright syndrome, 467–468 in osteopetrosis, 464 in Paget’s disease of bone, 461–462, 461f, 462f Radioiodine therapy for Graves’ disease, 82 for hyperfunctioning solitary thyroid nodule, 91 for malignant pheochromocytoma, 130 for thyroid cancer, 96–97 for toxic multinodular goiter, 91 Radioiodine uptake, in thyroid dysfunction evaluation, 70–71 Radionuclide scans/scintigraphy in carcinoid tumor, 360f in pancreatic endocrine tumors, 360–361 545 Raloxifene for gynecomastia, 162 for osteoporosis prevention and treatment, 452, 454f, 521 Ranitidine, adverse effects of, 227t RANK (receptor activator of NFκB), 442, 443f, 459, 460f RANKL, 442, 443f RAS gene, in thyroid cancer, 94t, 95 Rathke’s cyst, 25 Raynaud’s phenomenon, chemotherapyrelated, 176 Rb gene, in parathyroid carcinoma, 414 Receptor tyrosine kinase, 2t Rectal carcinoids, 345t, 349, 354 Reifenstein syndrome, 144–145 Remodeling, bone, 441–442, 441f Renal disease/failure See Chronic kidney disease (CKD) Renal osteodystrophy, 424 Renin, ectopic production of, 377t Renin-angiotensin-aldosterone (RAA) system, regulation of, 102–103, 103f Repaglinide, for diabetes mellitus, 298, 300t Reserpine, adverse effects of, 227t Resistance to thyroid hormone (RTH), 67t, 69 Respiratory disorders, obesity and, 242 Resting (basal) metabolic rate, 236 RET gene analysis of, 368–369 in MEN 2, 98, 130, 368–369, 369f, 414 in pheochromocytoma, 134, 134f in thyroid cancer, 94–95, 94t Retrograde ejaculation, 225, 284 Retroperitoneal lymph node dissection, for testicular cancer, 173, 175 Reverse T3 (rT3), 62f Rhabdomyolysis, hypocalcemia in, 405 Rho kinase, 224 Riboflavin (vitamin B2), reference range for, 484t Rickets diagnosis of, 400 vitamin D deficiency and, 400 vitamin D–dependent type I, 434 type II, 434 Riedel’s thyroiditis, 86 Rimonabant, 250 Risedronate adverse effects of, 454 in osteoporosis management/prevention, 453f, 454, 458, 521 for Paget’s disease of bone, 463t Roferon-A, 227t Rosiglitazone, for diabetes mellitus, 299t, 301 Rosuvastatin, for hyperlipidemia, 337t Roux-en-Y gastric bypass, 251, 251f, 525 RSPO1 gene, 146t rT3 (reverse T3), 62f RTH (resistance to thyroid hormone), 67t, 69 Runx2, 386 546 Saline infusion test, 113 Salpingo-oophorectomy, bilateral in endometrial cancer, 222 for ovarian cancer, 217 for ovarian germ cell tumors, 219 Salt-wasting 21-hydroxylase deficiency, 145 SAME (syndrome of apparent mineralocorticoid excess), 112 Sandostatin-LAR, for acromegaly, 41 Sanjad-Sakati syndrome, 431 Sarcoidosis hypercalcemia in, 403, 422 hypocalcemia in, 404 hypopituitarism in, 20 Sarcoma paraneoplastic syndromes in, 377t uterine, 221, 222 Saxagliptin, for diabetes mellitus, 299t, 300t Scleredema, diabetic, 288 Sclerosteosis, 465 SDHB gene, 131, 134, 134f SDHD gene, 131, 134, 134f Sedative-hypnotics, adverse effects of, 230t Selective estrogen response modulators (SERMs) action of, 452 in osteoporosis management/prevention, 452, 521 Selective serotonin reuptake inhibitors (SSRIs), adverse effects of, 226, 227t Selenium, reference range for, 484t Sella chordomas, 25 Sellar mass lesions, 25–26, 26t, 159 See also Pituitary tumors (adenomas) Semen analysis, 153, 188 Seminiferous tubules, 149f, 151–152 Sepsis, hypoglycemia in, 313 Septo-optic dysplasia, 19 Serine kinase receptors, 2t, Serotonin (5-HT) in carcinoid syndrome, 351 synthesis, secretion, and metabolism of, 342–343, 345f Sertoli-Leydig tumor, 218 Seven transmembrane GPCR family See G protein–coupled receptors (GPCRs) Sex chromosomal, 136, 136f gonadal, 136–137, 136f, 138f phenotypic, 138, 139f Sex cord tumors, ovarian, 218 Sex development components of, 136–138, 136f disorders of, 137t, 138 genetic regulation of, 138f normal, 136, 139f Sex hormone-binding globulin, 213 Sex therapy, 229 Sexual abuse, sexual dysfunction in adulthood following, 226, 230t Sexual arousal disorder, female, 231 Sexual dysfunction, 224 Sexually transmitted infections (STIs), cervical cancer and, 220 Index Sexual pain disorder, 231 Sexual response, physiology of female, 230–231 male, 224–225, 225f SF1 gene, 100, 142, 143t Sheehan’s syndrome, 20, 196, 487, 505 Short stature clinical features of, 37 diagnosis of, 37 etiology of, 36 nutritional, 37 psychosocial, 37 treatment of, 37 in Turner’s syndrome, 141 SIAD See Syndrome of inappropriate antidiuresis (SIAD) Sibutramine, 250, 258 Sick euthyroid syndrome, 67t, 86, 491, 508 Signal transduction pathways, membrane receptor families and, 2t Sildenafil action of, 224, 225f adverse effects of, 229 for erectile dysfunction, 228–229 Simvastatin adverse effects of, 337t for hyperlipidemia, 337t Sirolimus, therapeutic monitoring of, 483t Sitagliptin, for diabetes mellitus, 299t, 300t Sitosterolemia, 322t, 324–325, 523 Skeletal maturation, somatic growth and, 36 Skin cancer, paraneoplastic syndromes in, 377t Skinfold thickness, 234 Sleep deprivation, 237 Small intestine, carcinoid tumors of, 345t, 348–349, 349t Smith-Lemli-Opitz syndrome, 119t Smoking cervical cancer and, 220 erectile dysfunction and, 225 osteoporosis and, 445 Sodium loading test, 113 Somatostatin structure of, 352, 353f synthesis of, 35 Somatostatin analogues for acromegaly, 41–42, 41f adverse effects of, 42 for TSH-secreting adenomas, 49 Somatostatinoma, 357 clinical features of, 344t, 357 diagnosis of, 358 etiology of, 357–358 treatment of, 358 tumor location in, 344t Somatotrope, 16t, 23t Sorafenib, for thyroid cancer, 97 South Beach diet, 247 SOX3 gene, 120t SOX9 gene, 142, 143t, 146t Spermatogenesis, 149f, 151–152 Sperm banking, 177 Spinal cord disease/injury, erectile dysfunction in, 226 Spinobulbar muscular atrophy, 161 Spironolactone adverse effects of erectile dysfunction, 226, 227t female sexual dysfunction, 230t hyperkalemia, 214 hypotension, 214 for hirsutism, 214 for mineralocorticoid excess, 114 for polycystic ovarian syndrome, 197 Sporadic goiter, 88 Squamous cell carcinoma, endometrium, 222 SRY gene, 142, 143t, 146t Staphylococcus aureus infections, in diabetes mellitus, 288 StAR (steroidogenic acute regulatory protein), 142, 143t Statins adverse effects of, 336, 337t for lipoprotein disorders, 259, 336, 337t Sterilization (birth control), 190t, 191 Steroid(s), ovarian, 181–182, 182f Steroid hormones See also specific hormones actions of, 182 adverse effects of, 244 synthesis, metabolism, and action of, 103–105, 104f, 105f Steroidogenesis regulatory control of, 100–103, 102f two-cell model for, 181, 182f Steroidogenic enzyme pathways, disorders of, 142, 143t, 145 Stress, gonadotropin deficiency due to, 158 Stroke, prevention of, 204t, 206 Stromal tumors, ovarian, 218 Strontium ranelate, for osteoporosis, 457 Struma ovarii, 84, 377t Substernal goiter, 89 Sugar Busters diet, 247 Sulfonylureas adverse effects of, 244, 298 drug interactions of, 298 properties of, 300t Sunlight, vitamin D deficiency due to lack of, 433–434 Swyer syndrome, 142, 143t Sympathomimetics, ARR effects of, 115t Syndrome of apparent mineralocorticoid excess (SAME), 112 Syndrome of inappropriate antidiuresis (SIAD) differential diagnosis of, 59t, 60 etiology of, 58–59, 58t osmoregulatory dysfunction in, 57f pathophysiology of, 59–60 treatment of, 60–61 tumor-associated, 378 clinical features of, 378 diagnosis of, 378 etiology of, 378 treatment of, 378–388 Syndrome X See Metabolic syndrome T3 See Triiodothyronine (T3) T3-resin uptake test, 70 T4 See Thyroxine (T4) Tacrolimus, therapeutic monitoring of, 483t Index Tadalafil action of, 224, 225f adverse effects of, 229 for erectile dysfunction, 228–229 Tamoxifen adverse effects of, 221 for gynecomastia, 162 for osteoporosis prevention and treatment, 452 Tangier disease (ABCA1 deficiency), 329 Taxanes, for ovarian cancer, 217 TBG (thyroxine-binding globulin), 67t, 70 TCAs See Tricyclic antidepressants (TCAs) Telogen, 209 Teratoma ovarian, 218–219 parasellar, 26 testicular, 173, 177 Teriparatide, for osteoporosis prevention and treatment of, 456, 456f Testes/testicles, 148 acquired defects of, 160–161 atrophy of, in systemic disease, 160 biopsy of, 153 development of, 48 disorders of, 152 dysgenesis of, 142, 143t dysgenetic, 142, 143t regulation of function of androgen synthesis in, 149–150, 150f hypothalamic-pituitary-testis axis in, 149–150, 149f spermatogenesis and, 149f, 151–152 structure of, 48 Testicular adrenal rest tumors, 125, 126f Testicular cancer, 172 clinical features of, 172–173 epidemiology of, 172 etiology of, 172 genetic factors in, 172 incidence of, 172 nonseminoma, 173, 176t paraneoplastic syndromes in, 377t pathology of, 173, 174f risk classification in, 176, 176t seminoma, 173, 176t staging of, 173, 174f treatment of chemotherapy for advanced disease, 175–176 infertility after, 177 postchemotherapy surgery, 176 risk-directed chemotherapy, 176, 176t salvage chemotherapy, 177 stage I nonseminoma, 173, 174f, 175, 502–503, 523 stage II nonseminoma, 174f, 175 stages I and II seminoma, 174f, 175 tumor markers in, 173, 502, 523 Testicular feminization syndrome See Androgen insensitivity syndrome (AIS) Testicular mass, 172 Testicular torsion, testicular dysfunction due to, 160 Testosterone assays of, 153 bioavailable, 153 in hirsutism, 210–213 total, tests of, 153 transport and metabolism of, 150–151, 151f unbound, measurement of, 153 Testosterone gel, 165t, 166–167 Testosterone therapy abuse of, 170–171 adverse effects of, 168–170, 169t for age-related reproductive dysfunction, 162–163, 164–166 buccal adhesive testosterone, 165t, 167 contraindications to, 168, 169t for erectile dysfunction, 229 formulations not available in U.S., 167 for hypogonadism, 47 injectable forms of, 166, 166t male hormonal contraception and, 168 monitoring of, 168–170, 169t novel androgen formulations, 167 oral derivatives, 165t, 166 pharmacologic uses of, 167 pharmacology of, 165t regimens for, 168 testosterone gel, 165t, 166–167 transdermal patch, 165t, 166, 166t, 229 Testotoxicosis, 154 Tg See Thyroglobulin (Tg) THBR (thyroid hormone binding ratio), 70 Thecoma, of ovary, 218–219 Thelarche, 185 Theophylline, therapeutic monitoring of, 484t Thermogenesis, 236, 241 Thiamine (vitamin B1) for dysmenorrhea, 199 reference range for, 484t Thiazide diuretics adverse effects of, 226 erectile dysfunction, 227t hypercalcemia, 423 for nephrogenic diabetes insipidus, 56 Thiazolidinediones action of, 299t, 301 adverse effects of, 244, 299t for insulin resistance in metabolic syndrome, 260 for type diabetes mellitus, 299t, 301 Thionamides, for Graves’ disease, 81 Thirst defects in, 56–57 mechanism of, 52 Thymic cancer, paraneoplastic syndromes in, 377t Thyroglobulin (Tg) in congenital hypothyroidism, 63, 63t in thyroid cancer follow-up, 70, 97 in thyrotoxicosis, 70 Thyroid acropachy, 79f, 80 Thyroid cancer, 92 anaplastic, 93t, 98 classification of, 92–93, 92t, 93t follicular, 92t, 93t, 95, 96f follow-up care, 97, 97f 547 genetic factors in, 93–95, 94t incidence of, 92, 93f laboratory evaluation of, 92 medullary familial, 98 in MEN 2, 98, 368, 369f, 370–371 paraneoplastic syndromes in, 377t prevalence of, 92t staging of, 93t papillary, 92t, 93t, 95, 96f pathogenesis of, 93–95 in patients with thyroid nodule, 92, 93t risk factors for, 92, 93t screening and assessment of, 13t survival rates, 95, 96f treatment of kinase inhibitors, 97 radioiodine therapy, 96–97 surgery, 95–96 TSH suppression therapy, 96 well-differentiated, 92t, 93t, 95–98 Thyroid cysts, 92 Thyroid dermopathy, 79f, 80, 83–84 Thyroid disorders, 69 cancer See Thyroid cancer hyperthyroidism See Hyperthyroidism hypothyroidism See Hypothyroidism laboratory studies of radioiodine uptake and thyroid scanning, 70–71 Tg levels, 70 thyroid hormone measurement, 69–70 TPO antibodies, 70 ultrasonography, 71 lipoprotein disorders in, 331 nodular See Thyroid nodule Thyroidectomy for diffuse nontoxic goiter, 89 for Graves’ disease, 82–83 hypocalcemia following, 499, 518 Thyroid gland, 62 anatomy of, 62–63 development of, 62–63 function of, 87–88 hormones of See Thyroid hormone(s) pain in, differential diagnosis of, 84 physical examination of, 69 regulation of, 63 Thyroid hormone(s) action of, 68–69, 68f laboratory evaluation of, 69–70 resistance to, 67t, 69 structure of, 62f synthesis of, 64 factors influencing, 66 iodine metabolism and transport in, 64–65 organification, coupling, storage, release, 65–66 regulation of, 63–64, 64f TSH action in, 66 transport and metabolism of binding proteins in, 67 deiodinases in, 68 serum binding proteins in, 66–67, 66t unbound, 70 548 Thyroid hormone binding proteins, abnormalities of, 67–68 Thyroid hormone binding ratio (THBR), 70 Thyroid hormone receptors (TRs), 68–69, 68f Thyroiditis, 84 acute, 84, 84t atrophic, 72 chronic, 84t, 86 de Quervain’s, 84–85, 491, 508–509 destructive, 84 drug-induced, 86 etiology of, 84t goitrous, 72 granulomatous, 84–85 Hashimoto’s, 72 postpartum, 86 Riedel’s, 86 silent (painless), 85–86, 491, 508–509 subacute, 84–85, 84t, 85f viral, 84–85 Thyroid lymphoma, 98 Thyroid nodule approach to the patient, 98–99, 99f benign, 92, 92t prevalence of, 13t, 88 screening and assessment of, 13t, 491, 509 solitary, hyperfunctioning, 91–92, 91f thyroid cancer in patients with, 92, 93t Thyroid peroxidase (TPO) in autoimmune hypothyroidism, 70 in thyroid development, 63, 63t Thyroid response elements (TREs), 68, 68f Thyroid scanning, 71 Thyroid-stimulating hormone (TSH), 49 action of, 49 assessment of, 10 deficiency of, 23t, 49 ectopic production of, 377t elevated, 490, 507–508 laboratory evaluation of, 22t, 69 secretion of, 49 suppression therapy, 96 synthesis of, 49 thyroid cancer due to, 93 in thyroid gland function, 66 Thyroid-stimulating hormone receptor (TSH-R), 63, 63t, 91, 91f, 94t Thyroid-stimulating hormone (TSH)–secreting adenomas, 49 Thyroid-stimulating hormone (TSH)–secreting pituitary adenoma, 84 Thyroid-stimulating immunoglobulins (TSI) in Graves’ disease, 70 in pregnancy, 70 Thyroid storm (thyrotoxic crisis), 83 Thyrotoxicosis, 62, 77 See also Graves’ disease amiodarone-induced, 87–88 apathetic, 78 clinical features of, 78–80, 78t, 79f definition of, 77 etiology of, 77t, 84 primary hyperthyroidism and, 77t subclinical, 89 without hyperthyroidism, 77t Thyrotoxicosis factitia, 70, 84 Index Thyrotrope, 6t Thyrotropin-releasing hormone (TRH), 30, 40 Thyroxine (T4) characteristics of, 66t, 489, 507 free, 70 laboratory evaluation of, 69–70, 489, 507 structure of, 62f Thyroxine-binding globulin (TBG), 67t, 70 Tiludronate, for Paget’s disease of bone, 463t TIP39 (tubular infundibular peptide of 39 residues), 409 TNFRSF11A gene, 459 TNFRSF11B gene, 459 Tobacco use See Smoking Topiramate, 251 Topotecan, for ovarian cancer, 217 Total parenteral nutrition See Parenteral nutrition Toxic adenoma, 91–92, 91f Toxic multinodular goiter, 90–91 TP53 gene, 117 TPO See Thyroid peroxidase (TPO) Tranquilizers, adverse effects of, 227t Transforming growth factor-β (TGF-β), in thyroid hormone synthesis, 66 Transsphenoidal surgery for acromegaly, 41 for Cushing’s syndrome, 45, 111 for pituitary tumors, 28–29, 29f, 48 Transthyretin (TTR), euthyroid hyperthyroxinemia and, 67t Transvaginal ultrasound, in ovarian cancer, 216 Trastuzumab, for ovarian cancer, 218 TREs (thyroid response elements), 68, 68f TRH (thyrotropin-releasing hormone), 30, 49 Tricyclic antidepressants (TCAs) adverse effects of erectile dysfunction, 226, 227t obesity, 244 for diabetic neuropathy, 283 Triglycerides elevated, lipid disorders associated with, 325–328, 327t lowering level of, 259 normal, elevated LDL–C and, 321t, 322–325 of VLDLs, 321 Triiodothyronine (T3) characteristics of, 66t free, 70 laboratory evaluation of, 69–70 structure of, 62f Trilostane for Cushing’s syndrome, 46 TrkB gene, 238t Troglitazone, 301 Trousseau’s sign, 405, 518 True hermaphroditism See Ovotesticular disorders of sexual development T-scores, 439, 445, 445f TSH See Thyroid-stimulating hormone (TSH) TSH-R (thyroid-stimulating hormone receptor), 91, 91f, 94t TSI See Thyroid-stimulating immunoglobulins (TSI) TTF-1, 63, 63t TTF-2, 63, 63t Tubal disease, 189 Tubal ligation, 190t, 191 Tuberous sclerosis, 347t, 348 Tub gene, 238t, 239 Tubular infundibular peptide of 39 residues (TIP39), 409 Tumoral calcinosis, 469–470 Tumor lysis syndrome, hypocalcemia in, 405 Tumor markers in ovarian cancer, 216 in testicular cancer, 173 Tumor-suppressor genes, in thyroid cancer, 93–95, 94t Turner’s syndrome, 140 clinical features of, 140, 140t, 496, 515 pathophysiology of, 140 prevalence of, 13t primary ovarian insufficiency in, 197 screening and assessment of, 13t, 496, 515 treatment of, 141 Two-cell model for steroidogenesis, 181, 182f Type diabetes mellitus See Diabetes mellitus (DM), type Type diabetes mellitus See Diabetes mellitus (DM), type Tyrosine kinase receptors, 2t, 5f, UDCA (ursodeoxycholic acid), 249 Ulcer(s), foot, in diabetes mellitus, 287–288 Ultrasonography in bone mass measurement, 445 in thyroid dysfunction evaluation, 71 Uncoupling protein, mitochondrial, 236 Underandrogenization of 46,XY fetus, 142–146 Underwater weighing, 234 Underweight, 246t Urinary tract infections (UTIs), in diabetes mellitus, 288 Ursodeoxycholic acid (UDCA), 249 Uterus, disorders of amenorrhea in, 195–196, 196f cancer See Endometrial cancer pelvic pain in, 198 treatment of, 196 Vacuum constriction device, for erectile dysfunction, 229 Vagina blind, 195 congenital absence of, 147 Vaginal dilatation, 196 Vaginal ring, monthly, 190t, 192 Vaginal septum, 195 Valproate/valproic acid adverse effects of, 244 therapeutic monitoring of, 484t van Buchem’s disease, 465 Vancomycin, therapeutic monitoring of, 484t Vardenafil, 224, 225f, 228–229 Vascular endothelial growth factor (VEGF), in diabetic retinopathy, 278 Vasectomy, 190t, 191 549 Index Vasoactive intestinal peptide (VIP), 30, 358, 377t Vasoactive intestinal peptidomas (VIPomas) See VIPomas (vasoactive intestinal peptidomas) Vasointestinal polypeptide, in female sexual response, 231 Vasopressin See also Arginine vasopressin (AVP) ectopic production of See Syndrome of inappropriate antidiuresis (SIAD) VeIP regimen, for testicular cancer, 177 Velocardiofacial syndrome, hypocalcemia and, 430 Venlafaxine, for menopausal symptoms, 202 Venous stasis, obesity and, 243 Venous thromboembolism (VTE), postmenopausal hormone therapy and, 202, 203t Verner-Morrison syndrome, 365, 516 Vertebrae, “ivory,” 462, 522 Vertebral fractures bisphosphonates for prevention of, 452–454, 453f crush fracture, 440, 440f denosumab for prevention of, 455, 455f epidemiology of, 439f, 440 raloxifene for prevention of, 452, 454f teriparatide for prevention of, 455–456, 456f Vertebroplasty, 457 Very-low-calorie diet, 249 Very low–density lipoproteins (VLDLs) characteristics of, 317, 317f, 318t elevated levels of, 322t, 326, 327t metabolic pathways of, 319f, 320 VHL gene, 132–134, 134f, 371 Vildagliptin, for diabetes mellitus, 299t, 300t Vinblastine for gestational trophoblastic disease, 223 for testicular cancer, 177 Vincristine for gestational trophoblastic disease, 223 for malignant pheochromocytoma, 130 VIP (vasoactive intestinal peptide), 30, 358, 377t VIPomas (vasoactive intestinal peptidomas), 358 clinical features of, 344t, 358, 497, 516 diagnosis of, 358, 516 treatment of, 358–359 tumor locations in, 344t Viral orchitis, 160 Viral thyroiditis, 84–85 Virilization, 209 Visual loss, in pituitary tumors, 26 Vitamin(s), reference ranges for, 484t Vitamin A reference range for, 484t toxicity of, 423 Vitamin B1 See Thiamine (vitamin B1) Vitamin B2 (riboflavin), reference range for, 484t Vitamin B6 (pyridoxine), reference range for, 484t Vitamin B12 (cobalamin ), reference range for, 484t Vitamin C, reference range for, 484t Vitamin D, 396 activation of, 396–397, 397f defective metabolism of, 434, 498, 518 deficiency of anticonvulsants and, 434 clinical features of, 400 diagnosis of, 400, 405 in elderly, 399, 498, 517 etiology of, 399, 399t hypocalcemia and, 404 hypomagnesemia and, 396 inadequate diet and/or sunlight and, 433–434 osteomalacia due to, 400 osteoporosis associated with, 442–443 prevalence of, 13t, 399 rickets due to, 400 screening and assessment of, 13t, 518 terminal ileal disease and, 399 treatment of, 396, 401, 405 for hypocalcemia, 437–438 for hypoparathyroidism, 432 metabolism of, 396–397, 397f, 398f in osteoporosis management/prevention, 450 reference range for, 484t resistance to, 404, 434 supplements, for hypocalcemia, 405 synthesis of, 396–397, 397f, 398f toxicity of, 422 Vitamin E reference range for, 484t supplements for dysmenorrhea, 199 for menopausal symptoms, 202 Vitamin K for osteoporosis management/prevention, 450 reference range for, 484t VLDLs See Very low–density lipoproteins (VLDLs) von Hippel-Lindau disease clinical features of, 131, 132, 133f, 363t genetic factors in, 132–134, 347t, 348, 371 pancreatic endocrine tumors in, 347t, 348 pheochromocytoma in, 131, 132–134, 133f, 371 vs MEN or MEN 2, 371 von Recklinghausen’s disease See Neurofibromatosis type (NF1) VTE (venous thromboembolism), postmenopausal hormone therapy and, 202, 203t Waist circumference, 244, 246t in metabolic syndrome, 253t, 256 Waist-to-hip ratio, 242, 244 Water diuresis, 51, 51f Watery diarrhea syndrome, 365 Weight disease risk and, 246t regulation of, 235–236 set point of, 240 Weight gain, physiology of, 235–236 Weight loss for lipoprotein disorders, 335 for metabolic syndrome, 258 Whipple’s triad, 308, 495, 513 Whole-body thyroid scanning, for thyroid cancer follow-up, 97 Williams’ syndrome, 422–423 WNT1 gene, 146t Wolff-Chaikoff effect, 66, 83, 87 Woven bone, 386 Wrist fracture, 440 WT1 gene, 143t Xtreme computed tomography, in bone mass measurement, 445 46,XX disorders, 145, 146t, 147 46,XY disorders, 142–146, 143t, 144f Yoga, 199 Yolk sac tumor, of ovary, 218–219 Zoledronate (zoledronic acid) for hypercalcemia, 378, 404, 427t, 428 for osteoporosis management/prevention, 453f, 454 for Paget’s disease of bone, 463, 463t Zollinger-Ellison syndrome (ZES), 354 clinical features of, 344t, 354–355, 496, 515–516 diagnosis of, 355, 496, 515–516 epidemiology of, 344t MEN and, 355 pathophysiology of, 344t treatment of, 355–356, 367 tumor distribution in, 344t Zone diet, 247 Zonisamide, 251 Z-scores, 445, 445f ... 22 2 22 7 23 2 23 8 24 3 24 8 25 4 25 9 26 4 26 9 27 5 28 0 28 5 62 196 20 2 20 7 21 3 21 8 22 4 22 9 23 5 24 0 24 6 25 1 25 6 26 2 26 7 27 3 27 8 28 4 28 9 29 5 63 20 3 20 8 21 4 22 0 22 5 23 1 23 7 24 2 24 8 25 4 25 9 26 5 27 0 27 8 28 2... 28 2 28 7 29 3 29 9 304 64 20 9 21 5 22 1 22 7 23 2 23 8 24 4 25 0 25 6 26 2 26 7 27 3 27 9 28 5 29 1 29 6 3 02 308 314 65 21 6 22 2 22 8 23 4 24 0 24 6 25 2 25 8 26 4 27 0 27 6 28 2 28 8 29 4 300 306 3 12 318 324 66 22 3 22 9 23 5 24 1... 25 8 59 178 183 188 193 198 20 3 20 8 21 2 21 7 22 2 22 7 23 2 23 7 24 2 24 7 25 2 25 7 26 2 26 7 60 184 189 194 199 20 4 20 9 21 5 22 0 22 5 23 0 23 5 24 0 24 5 25 0 25 5 26 1 26 6 27 1 27 6 61 190 195 20 1 20 6 21 1 21 7 22 2