bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple endocrine neoplasia type 1
Authors: Thakker R.V.
Published: July 2011

Multiple endocrine neoplasia (1, 2) is characterized by the occurrence of tumours involving two or more endocrine glands within a single patient. The disorder has previously been referred to as multiple endocrine adenopathy (MEA) or the pluriglandular syndrome. However, glandular hyperplasia and malignancy may also occur in some patients and the term multiple endocrine neoplasia (MEN) is now preferred. There are two major forms of multiple endocrine neoplasia, referred to as type 1 and type 2, and each form is characterized by the development of tumours within specific endocrine glands (Table 6.11.1). Thus, the combined occurrence of tumours of the parathyroid glands, the pancreatic islet cells, and the anterior pituitary is characteristic of multiple endocrine neoplasia type 1 (MEN 1), which is also referred to as Wermer’s syndrome. However, in multiple endocrine neoplasia type 2 (MEN 2), which is also called Sipple’s syndrome, medullary thyroid carcinoma (MTC) occurs in association with phaeochromocytoma, and three clinical variants, referred to as MEN 2a, MEN 2b and MTC-only, are recognized (Table 6.11.1). Although MEN 1 and MEN 2 usually occur as distinct and separate syndromes as outlined above, some patients occasionally may develop tumours that are associated with both MEN 1 and MEN 2. For example, patients suffering from islet cell tumours of the pancreas and phaeochromocytomas or from acromegaly and phaeochromocytoma have been described, and these patients may represent ‘overlap’ syndromes. All these forms of MEN may either be inherited as autosomal dominant syndromes or they may occur sporadically, i.e. without a family history. However, this distinction between sporadic and familial cases may sometimes be difficult as in some sporadic cases the family history may be absent because the parent with the disease may have died before developing symptoms. In this chapter, the main clinical features and molecular genetics of the MEN 1 syndrome will be discussed.
Disorders of gonadotropin secretion
Authors: Berga Sarah L.
Published: July 2011

Folliculogenesis and ovulation depend upon adequate gonadotropin stimulation, which in turn requires appropriate gonadotropinreleasing hormone (GnRH) input. There exists a group of related disorders in which GnRH drive to the pituitary is reduced, resulting in secondary diminution of follicle-stimulating hormone (FSH) and luteinizing hormone input to the ovary. Clinically, reduced GnRH drive results in a spectrum of ovarian compromise, ranging from luteal insufficiency to chronic anovulation. Variable menstrual patterns follow, including amenorrhoea, polymenorrhoea, with or without menorrhagia, and oligomenorrhoea, depending on the extent of follicular activity across time. Rarely, there is an organic or congenital cause for reduced GnRH drive, such as a brain tumour, coeliac disease, or migration of an insufficient number of GnRH neurons from the olfactory placode into the hypothalamus during fetal development. Typically, the cause is functional, that is, due to the endocrine consequences of certain psychological or behavioural variables. Anorexia nervosa provides the most dramatic example, but most women who develop functional hypothalamic anovulation do not meet criteria for an eating disorder and do not develop one subsequently. Because of the occult and heterogeneous nature of the behavioural variables that contribute to the genesis of this related group of disorders, a variety of names have been used to describe this syndrome, including exercise amenorrhoea, stress-related or stress-induced anovulation, functional hypothalamic amenorrhoea, functional hypothalamic chronic anovulation, and psychogenic amenorrhoea. Occasionally, psychiatric syndromes other than eating disorders such as depression coexist with functional hypothalamic anovulation, but unlike anorexia nervosa, in which amenorrhoea is almost universal, amenorrhoea is less common in women with bulimia and depression. Despite the multiplicity of names, the pathogenesis of anovulation in these diverse clinical settings is similar. In recognition of their common nature, I have chosen herein to refer to this group of disorders as ‘functional hypothalamic anovulation’ or FHA. As noted above, not all women have reduced gonadotropin secretion to the extent that they become amenorrhoeic or even persistently anovulatory, but most investigations have focused on subjects with the most complete expression of these related disorders, namely, those who are amenorrhoeic due to chronic anovulation. Generally, functional hypothalamic anovulation is considered to be a form of secondary amenorrhoea, but it can present as primary amenorrhoea. The diagnosis of functional hypothalamic anovulation is one of exclusion.
The breast: lactation and breast cancer as an endocrine disease
Authors: Santen R.
Published: July 2011

This chapter discusses both benign breast lesions and those that associated with an increased risk of breast cancer development, as well as the aetiology, clinical and pathologic prognosis, and hormonal treatment of breast cancers.

Clinical observations in women suggest that hormones play a role in the aetiology of benign lesions. In postmenopausal women receiving oestrogens (with or without progestins) for more than 8 years, the prevalence of benign breast lesions is increased 1.7-fold; whilst the anti-oestrogen, tamoxifen, is associated with a 28 % reduction in prevalence of benign breast lesions. Cyclic and non-cyclic breast pain, nipple discharge and breast lumps are all clinical features of benign breast lesions.

A practical classification, based primarily on degree of proliferation, distinguishes benign breast lesions with no associated increase in breast cancer risk from those with a small or moderate (i.e. 1.1–2.0- fold), or high risk (higher than 2.0-fold). Women considered at high risk of developing breast cancer can be treated with selective oestrogen receptor modulators (SERMS) including tamoxifen and raloxifene, which have been shown to decrease breast cancer risk by approximately 50 % when compared to placebo.

The aetiology of breast cancer includes the accumulation of mutations of key genes involved in cell proliferation, DNA repair, vasculogenesis, invasion, metastasis, and apoptosis; dietary, environmental, and lifestyle factors also play a key role. The majority of risk factors for breast cancer relate to the duration or intensity of a woman’s exposure to endogenous or exogenous oestrogens; mitogenic and mutagenic effects of oestradiol probably act in concert to initiate and promote the breast cancer development.

In this chapter, a variety of established and newer methods for classifying established breast cancers and predicting their prognosis and response to hormonal treatment strategies are discussed. The mechanisms (blockade of oestrogen synthesis or function) of hormonal treatments are described, as is the development of resistance to these treatments. An overview of the clinical efficacy of different hormonal treatments for breast cancer is given, as are recommended approaches to hormonal treatment of breast cancer in pre- and post-menopausal women, and in advanced disease states.
Endocrine disease in pregnancy
Authors: Nelson C. , Germain S.
Published: July 2011

This chapter describes the causes, symptoms and clinical management strategies of endocrine disease in pregnancy, beginning with thyroid and parathyroid disease, then diabetes mellitus, pre-existing diabetes, gestational diabetes, adrenal diabetes and pituitary disease.
Sports endocrinology: the use and abuse of performance-enhancing hormones and drugs
Authors: Deftos Leonard John , Zeigler Mark
Published: July 2011

The endocrine system pervades all of sports, just as it pervades all of biology and medicine. The importance of endocrine glands and their hormonal products and effects in sports is axiomatic to the endocrinologist, and the actions in athletic activity of key hormones such as adrenaline are even known to much of the lay public. The other chapters in this textbook provided a systematic review of the effects of these hormones on organ systems, including those involved in sports as well as in health and disease. This chapter will only provide brief review of endocrine physiology that is relevant to sports. Such reviews can be readily found in other publications (1) as well as in the other chapters of this book. This chapter will instead focus on the role of hormones in the international sports arena, an arena that is populated by professional athletes, aspiring athletes, and the weekend warrior public of essentially all countries.

Unlike classic endocrinology, where primarily endogenous hormones play a role in both health and disease, exogenous hormones taken supraphysiologically as well as physiologically have a major role in contemporary sports endocrinology (2). Consequently, sports endocrinology often collides with the administrative, regulatory, and legal bodies that reside at its intersection with sports events (2, 3). While systematic research will inform the basis of much of this chapter, anecdotes taken from sport can also be provocative if not informative (3). For example, consider the role of thyroid hormone replacement in the athlete who has hypothyroidism, a situation recently manifest by a pitcher in major league baseball who had surgery for thyroid cancer. Without much research support, the temptation exists to try to enhance this athlete’s performance by increasing his thyroid hormone dose before he is scheduled to pitch. At the other end of this particular spectrum is the athlete who chronically abuses androgens. Cases that also challenge the endocrinologist can fall in between these two extremes, such as glucose regulation for a diabetic footballer between games and during games and the cricketer who uses amphetamines intermittently.

While the use of hormones is at the centre of classic endocrinology, the medical periphery that is the ambit of some of sports endocrinology lurches beyond, into exercise pills and gene doping (1–4). It will become apparent that there is a paucity of controlled studies that demonstrate performance-enhancing effects of most of the agents abused by athletes (5). However, when all of the evidence is examined, exogenous androgens and perhaps growth hormone do seem to enhance athletic performance.
Metastatic disease in endocrine organs
Authors: Monteiro Michael , Lowe David
Published: July 2011

The term metastasis of a neoplasm refers to the spread of a previously localized, cohesive malignant tumour to a site distant from its site of origin with no contiguity with the primary site. The concept of metastases of lymphoma is a difficult one; a deposit in an organ of lymphoma is usually considered to be a component of generalized involvement by lymphoma rather than of metastatic spread. This chapter will focus on metastases in endocrine organs from carcinomas and sarcomas other than lymphoma.
Assessment and management of severe obesity in childhood and adolescence
Authors: Weiss Ram
Published: July 2011

The true prevalence of obesity in childhood is difficult to determine as there is no internationally accepted definition of pathological adiposity in the paediatric age group. Body weight is reasonably well correlated with body fat but is also highly correlated with height, and children of the same weight but different heights can have differing amounts of adiposity. In children the relationship between body mass index (BMI) and body fat varies considerably with age and with pubertal maturation. BMI centile charts using national BMI reference data have now been published in several countries and aid the graphical plotting of serial BMI measurements in individual patients. However, such charts are often based on arbitrary statistical measures and not on biological data related to the risk of later morbidity. Cole et al. developed age- and gender-specific cut-off lines from BMI data derived from six countries, which extrapolate risk from the adult experience to children (1). The International Obesity Task Force (IOTF) has recommended the use of these age- and gender-specific BMI cut-offs (overweight as approximately 91st percentile or greater and obesity as approximately 99th percentile or greater) for the comparison of obesity prevalence in different populations (2). Although there is no accepted definition for severe obesity in childhood, a BMI SD >2.5 (weight off the chart) is often used in specialist centres and the crossing of weight percentile lines upwards is an early indication of the risk of severe obesity.
Disorders of carbohydrate metabolism
Authors: Lachmann Robin H.
Published: July 2011

Many disorders of carbohydrate metabolism are characterized by hypoglycaemia and attacks of neuroglycopenia. Hypoglycaemia can also be caused by disorders affecting the use of other fuels, such as those producing fatty acids and ketone bodies which are important alternative sources of energy. Thus when investigating a patient with hypoglycaemia it is necessary to investigate not only pathways that provide glucose directly, but also those which spare glucose utilization and thus provide defence mechanisms when carbohydrate energy sources become depleted. The defence mechanisms that are activated during fasting to preserve blood glucose are:

◆ glycogenolysis—glucose liberation from glycogen degradation

◆ gluconeogenesis—glucose production from pyruvate/lactate and from noncarbohydrate sources such as glucogenic amino acids and glycerol

◆ fatty acid β‎-oxidation—catabolism of triglycerides to acetyl-CoA and ketone bodies

The interrelation between these glucose generating pathways is shown in Fig. 12.3.1.1.

Although there is much overlap, the activation of these defence mechanisms during fasting is sequential. The first defence mechanism, glycogenolysis, is exhausted within 8–12 h of fasting. The second and third defence mechanisms provide glucose once glycogen stores have been depleted. In a patient with glycogen storage disease (GSD) where glycogenolysis is blocked, gluconeogenesis and fatty acid oxidation are activated immediately on fasting and can only maintain normoglycaemia for a few hours. In patients with defects affecting gluconeogenesis or fatty acid oxidation, hypoglycaemia does not occur until glycogen stores have been depleted. When more than one pathway is affected, as in GSD I, where neither glycogenolysis nor gluconeogenesis can release glucose into the circulation, patients can be entirely dependent on oral carbohydrate intake to maintain normoglycaemia. These pathways are also susceptible to hormonal influences. Insulin in particular inhibits all three pathways and stimulates some enzymes of the reverse pathways: glycogen synthesis, glycolysis, and fatty acid synthesis. Therefore hyperinsulinaemia of whatever cause leads to severe hypoglycaemia which is resistant to treatment. Other hormones, such as glucagon, adrenaline, and growth hormone, also activate some enzymes of glucose homoeostasis, though less markedly. This is discussed elsewhere.

The metabolism of the other monosaccharides, galactose and fructose, is connected with that of glucose. As well as causing hypoglycaemia, inherited defects that affect the metabolism of these sugars lead to the accumulation of toxic metabolites which also contribute to pathology (see below).
Haemochromatosis
Authors: Allen K.J.
Published: July 2011

Hereditary haemochromatosis is an inherited iron storage disorder in which altered iron metabolism leads to an increase in intestinal iron absorption. This results in a progressive accumulation of body iron stores particularly in the liver, heart, pancreas, and pituitary. The excess iron deposited in tissues may result in cirrhosis, diabetes, cardiac failure and arrhythmias, hypogonadism, arthritis, hepatocellular carcinoma, and a shortened life expectancy.
Closing the loop
Authors: Hovorka Roman
Published: July 2011

The standard therapy of type 1 diabetes is based on multiple daily injections of short- and long acting-insulin analogues accompanied by blood glucose self-monitoring. However, treatment goals identified by the Diabetes Control and Complications Trial are difficult to achieve due, at least in part, to a high risk of hypoglycaemia associated with many currents forms of intensive insulin therapy.

Recent technological developments in real-time subcutaneous continuous glucose monitoring (CGM), combined with the continuous subcutaneous insulin infusion (CSII), could potentially reduce this risk. Since late 1990s at least five continuous or semicontinuous glucose monitors have received regulatory approval (1). CGM has been shown to improve glycaemic control in adults with type 1 diabetes, although apparent barriers to effectiveness in children and adolescents remain to be identified (see Chapter 13.4.9.1) (2). The availability of commercial CGM devices has reinvigorated research towards closed-loop systems (3-6), in which insulin is delivered according to real-time needs, as opposed to open-loop systems, which lack real-time responsiveness to changing glucose concentrations. Closed-loop insulin delivery, in which the insulin delivery is informed by the measured glucose concentrations has the potential gradually to revolutionize the management of type 1 diabetes by reducing or eliminating the risk of hypoglycaemia while achieving near-normal glucose levels.

A closed-loop system, also called the ‘artificial pancreas’, comprises three components: a CGM device to measure real-time glucose concentration, a titrating algorithm to compute the amount of insulin needed, and an insulin pump delivering a rapid-acting insulin analogue (see Fig. 13.4.9.2.1). Only a few prototypes have been developed. Progress has been hindered by suboptimal accuracy and reliability of CGM devices, the relatively slow absorption of subcutaneously administered ‘rapid’-acting insulin analogues, and the lack of adequate control algorithms. So far, testing has been confined to the clinical setting. However, a concentrated effort

promises an accelerated progress towards home testing of closed-loop systems. The research focus centres on systems utilizing subcutaneous glucose sensing and subcutaneous insulin delivery. This approach has the greatest potential for a near-future commercial exploitation, although other approaches utilizing intraperitoneal or intravenous sensing/delivery are, in principle, also feasible.
Diabetic ketoacidosis in childhood and adolescence
Authors: Silink M.
Published: July 2011

Diabetic ketoacidosis (DKA) may occur at the time of diagnosis of diabetes, or at any time subsequently. It is the cause of very significant morbidity and remains the most common cause of death in childhood and adolescent diabetes (1–3). For a discussion of DKA in adults, see Chapter 13.4.10.1.

Type 1 diabetes occurs in childhood (see Chapter 13.4.7) with an incidence that varies from more than 40 per year per 1 00 000 children under the age of 15 years old (in Finland), to less than 1 per 1 00 000 (in Asia). The mean age at diagnosis is usually 10–12 years old, although, in a number of countries, this seems to be declining. The younger the child is at diagnosis, the more aggressive the autoimmune-mediated destruction of the pancreatic β‎ cell, and the more rapid the progression to complete insulin dependence (see Chapter 13.2.3). Children are thus more liable to DKA than adults. Furthermore, children experience more viral infections than do adults, and the metabolic stresses associated with these infections increase their risk of developing DKA.

DKA has traditionally been considered to occur only in type 1 diabetes, but is now being reported in at least 25% of (usually obese) adolescents with newly diagnosed type 2 diabetes, especially when there are associated stress factors, such as infection (4, 5). Although the vast majority of diabetes in childhood and adolescence is type 1 diabetes, there has been a worldwide trend to the earlier development of type 2 diabetes in association with the overweight and obesity epidemic, especially in certain at-risk ethnic groups, e.g. Asians, African Americans, Hispanic Americans; see Chapter 13.4.3.1. The treatment of DKA in these patients is the same as for those with type 1 diabetes; however, the subsequent course of the treatment usually differs, and most patients are able to stop insulin and be treated with oral hypoglycaemic agents, weight reduction, exercise, and an appropriate food plan.
Pathogenesis of microvascular disease
Authors: Shore Angela C.
Published: July 2011

Disturbed microvascular function precedes clinically apparent microvascular complications. Complications are not confined to the eye and the kidney; they occur in many tissues, e.g. the heart and brain. Microvascular complications are the result of the combined effects of hyperglycaemia and haemodynamic factors on cells, modulated by genetic predisposition (Fig. 13.5.1.1). The intracellular pathway involved varies with the stage (i.e. whether in the initiation or progressive phase) and organ (kidney, eye), and may be modified by treatment. This chapter describes the generic factors involved in the pathogenesis of microvascular complications. Further details are available in recent reviews (1–10).
Diabetic nephropathy
Authors: Karalliedde Janaka , Janaka Giancarlo
Published: July 2011

Diabetic nephropathy is classically defined as a rise in urinary albumin excretion rate (UAER), often associated with an increase in blood pressure, with concomitant retinopathy but without evidence of

other causes of renal disease (1). It is characterized by a progressive decline in glomerular filtration rate (GFR), eventually resulting in end-stage renal disease. Diabetic nephropathy occurs in approximately 30–35% of type 1 and type 2 patients and tends to cluster in families. These families also show a predisposition to cardiovascular disease and hypertension—and, hypertension, or a predisposition to it, appears a major determinant of diabetic renal disease. These data taken together clearly suggest an individual susceptibility to this complication.

The phases of diabetic nephropathy based on urine albumin excretion status and GFR are shown in Table 13.5.3.1 (2). Histological changes of diabetic glomerulopathy are present in over 95% of patients with type 1 diabetes and albuminuria (UAER >300 mg/day) and in approximately 85% of type 2 diabetic patients who develop albuminuria with concomitant diabetic retinopathy (1, 2). In the absence of diabetic retinopathy nearly 30% of patients with type 2 diabetes and proteinuria have nondiabetic renal lesions (1).

The all-cause mortality in patients with diabetic nephropathy is nearly 20–40 times higher than that in patients without nephropathy. In recent years it has become apparent that renal disease and cardiovascular disease are closely related and diabetic nephropathy is acknowledged as an independent and powerful risk factor for cardiovascular disease (3). Many patients with diabetes and renal impairment die from a cardiovascular disease event before they progress to end-stage renal disease. Diabetic nephropathy is the most common cause of end-stage renal disease worldwide and represent about 30–40% of all patients receiving renal replacement therapy in the Western World.
Molecular pathogenesis of pituitary tumours
Authors: Donangelo Ines , Melmed Shlomo
Published: July 2011

Pituitary adenomas are discovered in up to 25% of unselected autopsies, however, clinically apparent tumours are considerably less common. The pituitary gland is composed of differentiated cell types: somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and gonadotrophs. Tumours may arise from any of these cell types and their secretory products depend on the cell of origin. The functional classification of pituitary tumorus is based on identification of cell gene products by immunostaining or mRNA detection, as well as measurement of circulating tumour and target organ hormone levels. Oversecretion of adrenocorticotropic hormone (ACTH) results in cortisol excess with Cushing’s disease. Growth hormone overproduction leads to acromegaly with typical acral overgrowth and metabolic abnormalities. Prolactin hypersecretion results in hypogonadism and galactorrhoea. Rarely, thyroid-stimulating hormone (TSH) hypersecretion leads to goitre and thyrotoxicosis, and gonadotropin excess results in gonadal dysfunction (1). Mixed tumours cosecreting growth hormone with prolactin, TSH, or ACTH may also arise from single cells. Clinically nonfunctional tumours are those that do not efficiently secrete their gene products, and most commonly they are derived from gonadotroph cells. Pituitary tumours are further defined radiographically as microadenomas (<1 cm in diameter) or macroadenomas (>1 cm in diameter). However, this classification does not reflect whether the pituitary tumour is amenable to total resection and limits assessment of invasive progression during serial imaging. Therefore, it is useful to apply the classification proposed by Hardy in 1973 and modified by Wilson in 1990 (Table 2.3.2.1), whereby pituitary tumours are classified into one of five grades and one of six stages, providing important preoperative information.

Pituitary tumours cause morbidity by both abnormal hormone secretion as well as compression of regional structures. As a considerable proportion of patients do not achieve optimal therapeutic control of mass effects and/or hormone hypersecretion despite advances in therapeutic approaches, understanding pathogenesis and pituitary tumour growth patterns in individual patients will enable identification of subcellular treatment targets, ultimately decreasing tumour-related morbidity and mortality.

Determinants of initiation and progression of pituitary adenomas are not fully understood. This chapter describes a spectrum of mechanisms implicated in pituitary tumorigenesis, including the role of pituitary plasticity, imbalances in cell cycle regulation, transcription factors, signalling pathways, and angiogenesis (Fig. 2.3.2.1). Molecular events related to tumorigenesis in human pituitary adenoma subtypes are summarized in Table 2.3.2.2. The causal role for selected genetic imbalances leading to development of pituitary tumours has been confirmed in several transgenic mouse models (Table 2.3.2.3).
Surgery of pituitary tumours
Authors: Dunn Ian F. , Laws Edward R.
Published: July 2011

Pituitary tumours have both endocrine and neuro-oncologic sequelae. Secretory tumours may liberate physiological hormones to pathological excess, generating a full spectrum of metabolic aberrations and hallmark clinical syndromes. Other pituitary tumours are endocrinologically inactive and generate instead a variety of compressive phenomena such as pituitary hypofunction and neurological compromise. Although advances continue to be made in the pharmacological and radiotherapeutic management of pituitary tumours, surgery remains the treatment of choice for most of these lesions. Of the available surgical options, the transsphenoidal route is the dominant surgical approach to these tumours. Shaped by the brilliant insight of individual surgeons and technological innovation, transsphenoidal surgery for the sellar and parasellar regions is a fascinating chronicle in surgical history whose evolution continues unabated. We herein review surgical approaches to pituitary tumours, emphasizing the transsphenoidal approach.
Pituitary radiotherapy
Authors: Ajithkumar Thankamma , Brada Michael
Published: July 2011

External beam radiotherapy remains an important component of management of patients with pituitary adenoma and a considerable proportion of patients receive it during the course of their illness. Traditional policy had been to use radiotherapy for all patients with residual nonfunctioning pituitary adenoma after surgery as the majority were considered to progress (1). With improvement in surgical techniques and access to MRI, postoperative radiotherapy is no longer routinely employed even in the presence of residual tumour. The use of radiotherapy is based on relative risk assessment, generally withholding further treatment until progression unless there is a perceived threat to function, particularly vision, if the tumour was to progress. Currently radiotherapy is used in patients with progressive nonfunctioning adenoma demonstrated on interval imaging and achieves tumour control in over 90% of patients at 10 years and 85–92% in 20 years (1–9). Radiotherapy remains an integral component of treatment of patients with secreting adenoma who fail to achieve biochemical cure following surgery and medical treatment and in patients with progressive/recurrent tumour mass regardless of the status of hypersecretion. The slow rate of decline in hormone levels means that normalization takes months to years and the delay is primarily related to pretreatment hormone levels. Nevertheless radiotherapy leads to normalization of excess hormone secretion in the majority of patients.

The past two decades have seen developments in radiotherapy, which can largely be considered as refinement of existing technology. The principal aim of modern high-precision, localized radiotherapy is to treat less normal tissue to significant radiation doses therefore minimizing the risk of late normal tissue injury. The higher precision relies on increased accuracy of tumour delineation using modern imaging. The overall success of modern high-precision treatment is more likely to be related to the treatment centre infrastructure and expertise and the accuracy in identifying the tumour than the exact equipment used.
Acromegaly
Authors: Wass John A. H. , Trainer Peter J. , Korbonits Márta
Published: July 2011

Acromegaly is the condition most often associated with an anterior pituitary tumour, which results from growth hormone and insulin-like growth factor 1 (IGF-1) excess. It causes most characteristically enlargement of the hands and feet (Greek: akron, extremities; megas, great). Gigantism, which is the juvenile counterpart of acromegaly, is also caused by a pituitary tumour secreting growth hormone, but it causes excessive growth before epiphyseal fusion. It occurs less frequently than acromegaly because pituitary tumours in children are much less common than in adults.
Craniopharyngiomas
Authors: Karavitaki Niki
Published: July 2011

Craniopharyngiomas are rare tumours with a reported incidence of 0.13 cases per 100 000 person-years. They account for 2–5% of all the primary intracranial neoplasms, 5.6–15% of the intracranial tumours in childhood populations, in which they are the commonest lesion involving the hypothalamo-pituitary region. They may be detected at any age, even in the pre- and neonatal periods and almost half of the total cases have been described in adults. They show a bimodal age distribution with peak incidence rates in children aged 5–14 and adults aged 50–74 years (1).
The endocrine response to stress
Authors: Henley David E. , Kaye Joey M. , Lightman Stafford L.
Published: July 2011

In the face of any threat or challenge, either real or perceived, an organism must mount a series of coordinated and specific hormonal, autonomic, immune, and behavioural responses that allow it to either escape or adapt (1–3). To be successful, the characteristics and intensity of the response must match that posed by the threat itself and should last no longer than is necessary. A response that is either inadequate or excessive in terms of its specificity, intensity or duration may result in one or more of a multitude of psychological or physical pathologies (2–5). This concept of threat and the organism’s response to it is frequently recognized and understood as ‘stress’ but is so diverse that it lacks a universally accepted definition (2) and thus is difficult to investigate or study (6).

In the early 1900s, Walter Cannon introduced the concept of homoeostasis (4)—an ideal steady state for all physiological processes. Stress has been defined as the state where this ideal is threatened. More easily appreciated, however, are those factors, both intrinsic and extrinsic, which represent a challenge to homoeostasis (termed stressors) and the complex physiological, hormonal, and behavioural responses that occur to restore the balance, the stress response (1). The importance of endocrine systems in this stress response was emphasized by Hans Selye (7), who described the need for multiple, integrated systems to respond in a coordinated fashion following exposure to a particular stressor. Nonspecific activation of the hypothalamic–pituitary–adrenal (HPA) and sympatho-adrenomedullary (SAM) axes occurred following initial exposure to a noxious stimulus. Continued exposure to the same agent has been shown to have lasting and damaging effects on various endocrine, immune, and other systems, although recovery from this state was possible provided the stress was terminated (7). In addition to various noxious agents, numerous potential stressors exist including exertion, physical extremes, trauma, injury, and psychological stress. Indeed, psychological stressors are some of the most potent stimuli of the endocrine stress response particularly when they involve elements of novelty, uncertainty, and unpredictability. This has been highlighted by the observation that anticipating an event can be as potent an activator of the stress response as the event itself (7).
Thyroid imaging: nuclear medicine techniques
Authors: McDougall I. Ross , Iagaru Andrei
Published: July 2011

Thyroid imaging with radio-isotopes of iodine provides functional and quantitative information. Images, scans, or scintiscans are the terms used for the pictures that are obtained. In general, a radionuclide or radiopharmaceutical is administered orally or intravenously and images of the distribution of the radioactive tracer are obtained after specific times using a gamma camera. Some clinicians employ a rectilinear scanner rather than a gamma camera to produce the images, but this should not be considered state of the art. Scintiscans do not have the resolution of ultrasonography, CT, or MRI, but they provide reasonable anatomical information as well as functional information. A numerical uptake measurement of how much of the tracer has been trapped can be obtained at the same time as the scintiscan to provide complementary quantitative information. Imaging with radio-iodine is of great value in the diagnosis and management of patients with thyrotoxicosis and differentiated thyroid cancer. It is of less value in thyroid nodules, hypothyroidism, simple goitre, and undifferentiated thyroid cancer. The chapter starts with a discussion of the radioactive tracers and the methods for scanning. Then the appearance of a normal scan followed by findings in patients with thyrotoxicosis, simple goitre, nodular goitre, and congenital defects are described. In these situations the scintiscan evaluates the region of the thyroid. Finally, the role of nuclear medicine imaging in patients with cancer of the thyroid is presented separately since the imaging is different in that it usually evaluates the whole body.
Iodine deficiency disorders
Authors: Zimmermann Michael B.
Published: July 2011

Iodine (atomic weight 126.9 g/mol) is an essential component of the hormones produced by the thyroid gland. Thyroid hormones, and therefore iodine, are essential for mammalian life (1). The native iodine content of most foods and beverages is low, and the most commonly consumed foods provide 3–80 μ‎g/serving (1). The major dietary sources of iodine in the United States of America and Europe are bread and milk (2). Boiling, baking, and canning of foods containing iodized salt cause only small losses (≤10%) of iodine content. The iodine content in foods is also influenced by iodine-containing compounds used in irrigation, fertilizers, livestock feed, dairy industry disinfectants, and bakery dough conditioners. The recommendations for iodine intake by age and population group (3) are shown in Table 3.2.3.1.
Thyroiditis
Authors: Kaplan Beth , Pearce Elizabeth N. , Farwell Alan P.
Published: July 2011

Thyroiditis comprises a diverse group of disorders that are among the most common endocrine abnormalities encountered in clinical practice. These disorders range from the extremely common chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) to the extremely rare invasive fibrous thyroiditis (Riedel’s thyroiditis) (Box 3.2.7.1). Clinical presentations are also diverse, ranging from an incidental finding of a goitre to potentially life-threatening illness, from hypothyroidism to thyrotoxicosis. The term ‘thyroiditis’ implies that the disorders described in this section are inflammatory processes involving the thyroid gland. However, some of the lesions are not inflammatory, but are included in the thyroiditis category largely for convenience. A rational approach to such patients, including history, physical examination, laboratory evaluation, radionuclide or ultrasonographic imaging, and fine-needle aspiration biopsy, will allow the appropriate diagnosis to be made in the vast majority of cases.

This chapter will review the following forms of thyroiditis: Hashimoto’s, subacute, infectious, and Riedel’s. Other forms of thyroiditis are discussed within other chapters, as follows: postpartum thyroiditis (Chapter 3.4.6), radiation thyroiditis (Chapter 3.2.5), drug-induced thyroiditis (Chapter 3.1.4), thyroiditis associated with neoplasms (Chapter 3.5.5), and focal thyroiditis associated with nontoxic nodular goitre (Chapter 3.5.1).
Thyrotoxic periodic paralysis
Authors: Kung Annie W.C.
Published: July 2011

The association of thyrotoxicosis and periodic paralysis was first described in 1902 in a white patient. However, it soon became evident that thyrotoxic periodic paralysis (TPP) affects mainly Asian populations, in particular Chinese and Japanese, although isolated cases have also been reported in other ethnic groups such as white, Hispanic, African-American, and American Indian populations. The incidence of TPP in non-Asian thyrotoxic patients is around 0.1%, whereas in Chinese and Japanese thyrotoxic patients, TPP affects 1.8% and 1.9%, respectively (1–3). Despite a higher incidence of thyrotoxicosis in women, TPP affects mainly men, with a male to female ratio ranging from 17:1 to 70:1, according to different series. In the Chinese population, TPP affects 13% of male and 0.17% of female thyrotoxic patients. In the Japanese population, TPP was reported to occur in 8.2% of male and 0.4% of female thyrotoxic patients in the 1970s, but in 1991 the reported incidence had decreased to 4.3% and 0.04%, respectively (4).
Myxoedema coma
Authors: Klubo-Gwiezdzinska Joanna , Wartofsky Leonard
Published: July 2011

Myxoedema coma is the extreme expression of severe hypothyroidism and fortunately is quite rare. The first reported case appears to have been in 1879 by Ord from St Thomas’s Hospital, London. Two other patients who died in a hypothyroid coma were reported in 1888 in the proceedings of the Clinical Society of London (1). The next cases in the literature appeared in 1953 (2, 3), and some

300 cases have since been reported. Epidemiological data indicate an incidence rate of 0.22/1 000 000 per year (4). The most common presentation of the syndrome is in hospitalized elderly women with long-standing hypothyroidism, with 80% of cases occurring in women over 60 years of age. However, myxoedema coma occurs in younger patients as well, with 36 documented cases occurring during pregnancy (5, 6). In spite of early diagnosis and treatment, the mortality rate may be as high as 40–60%.
Pathogenesis of thyroid cancer
Authors: Mihailescu Dan , Schneider Arthur B , Fogelfeld Leon
Published: July 2011

Both epidemiological and molecular biological studies have been used to understand the origins of thyroid cancer. Epidemiological studies have been used to identify factors that predispose to thyroid cancer. That is principally how we know that exposure to radiation leads to thyroid cancer (see Chapter 3.2.5). In fact, radiation is the only environmental factor for which the proof is incontrovertible. Molecular biological studies, reviewed in the second part of this chapter, have been used to investigate the events within thyroid cells that are initiated by predisposing factors, e.g. radiation, and lead, by one or multiple steps, to transformation and cancer. These studies have focused on cancer-related genes, particularly proto-oncogenes and tumour suppressor genes, and have led to the identification of potential therapeutic agents. They have also focused on the cellular pathways and processes, including epigenetic changes and microRNA expression, which accompany transformation of the thyroid cell. Epidemiology and molecular biology have interacted productively in the studies that have followed the Chernobyl accident. This interaction is described in the third part of this chapter in which the mutations found in radiation-related thyroid cancers are reviewed.
Pathology of thyroid cancer
Authors: Oertel Yolanda C.
Published: July 2011

The majority of thyroid cancers arise from the follicular epithelium, are usually well differentiated, and thus many have a follicular architecture with varying amounts of colloid present. Medullary carcinoma constitutes a minority of thyroid cancers and arises from the C cells.

Fine-needle aspiration (FNA) biopsy is the accepted diagnostic test to determine whether a thyroid nodule is benign or malignant (1, 2). The role of the cytopathologist in the interpretation of smears has been considered crucial, and I believe this is partially valid. Based upon 30 years of experience as an ‘interventional pathologist’ who performs and interprets many aspirates, I emphasize that the quality of the sample is the crucial factor. The pathologist’s interpretation is only as good as the sample he/she obtains or receives, and not enough attention has been paid to the technique of aspiration. I have trained numerous physicians to perform FNAs in a skilful fashion in a short period of time, and I refer the reader to my previous publications (3–5). The high rate of ‘unsatisfactory specimens’ reported in the literature is concerning. This was discussed at the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference in October 2007 (6) and it was recommended that ‘at the end of training and for re-credentialing 90% diagnostic samples should be documented’. Please note that FNA biopsy should not be confused with needle biopsies (e.g. Tru-cut, Vim-Silverman, etc.) that yield tissue fragments that are processed for histological diagnosis.

The usual classification of thyroid cancers is founded on their histological and cytological features, many of which have been correlated with the clinical behaviour of the tumours. In addition, the age of the patients and the extent of the tumours are particularly important to determine the prognosis. The classification I follow is that of the WHO (7) with some of the modifications by the Armed Forces Institute of Pathology (AFIP) (8). My discussion will be focused largely on the most common types (see Box 3.5.5.1). Prolonged follow-up of the patients and extensive modern studies

of the tumours indicate that papillary carcinomas and follicular carcinomas have histological similarities and are usually of a low grade of malignancy, but they also have a variety of inherent differences.
Sex determination and differentiation
Authors: Warne Garry L. , Hewitt Jacqueline K.
Published: July 2011

A baby’s sex––one of its primary identifying features—is usually decided on the basis of a very brief inspection of the external genitalia completed by the birth attendant in the space of a few seconds. If there is a penis, the baby is declared to be a boy. If, instead, there is no penis and the genital folds are separated by a cleft, it is a girl. Recognizing the difference between male and female is easy when appearances are absolutely typical. Once in every 4500 births, however, it is impossible to say whether the baby is a boy or a girl because the genitalia are quite atypical or, in other words, ambiguous (1). In other cases, the external genitalia appear male or female, but the child is subsequently discovered, perhaps in the course of investigating or treating an inguinal hernia, to have internal anatomy normally associated with the opposite sex. For example, a female (with complete androgen insensitivity) can be born with testes and a male (with persistent Müllerian duct syndrome) can be born with fallopian tubes and a uterus. Other children are born with incompletely differentiated gonads that are neither typical testes nor ovaries; and may even contain elements of both, termed ovotestes. Chromosomes are no certain guide to sex either, as one in every 250 people has a major variation in the number of sex chromosomes (2). It is also possible to be chimeric, for example, 46,XX/46,XY.
Management of differences and disorders of sex development in the newborn
Authors: Ahmed S. Faisal , Midgley Paula , Rodie Martina
Published: July 2011

The birth of a new baby is one of the greatest wonders of nature. The first question that is usually posed by the new parent is 'is it a boy or a girl?'; without this information the parents cannot even formulate the second question, which is usually 'is he/she alright?'. It is no wonder that the birth of a child with an abnormality of genital development where the sex of rearing is uncertain at birth, presents difficult clinical and ethical issues. However, the recognition of genital ambiguity may depend on the expertise of the observer. The prevalence of genital anomalies at birth may be as high as 1 in 300 births (1), the prevalence of complex anomalies that may lead to true genital ambiguity may be as low as 1 in 5000 births (2). Rather than treating every affected child as a medical emergency, it is paramount that such a child is first assessed by an expert with adequate knowledge about the range of variation in the physical appearance of genitalia, the underlying pathophysiology of disorders of sex development, and the strengths and weaknesses of the tests that can be performed in early infancy. This expert should be able to ensure that the parents’ needs for information are comprehensively addressed, while appropriate investigations are performed in a timely fashion. This expert also needs to have immediate access to the multidisciplinary team that is essential for the management of such a child. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.