bluuebunny/crossref_metadata_2025 huggingface dataset:
Biosynthesis, transport, metabolism, and actions of thyroid hormones
Authors: Visser Theo J.
Published: July 2011

In healthy humans with a normal iodine intake, the thyroid follicular cells produce predominantly the prohormone thyroxine (3,3′,5,5′-tetraiodothyronine; T4), which is converted in peripheral tissues to the bioactive hormone 3,3′,5-triiodothyronine (T3) or to the inactive metabolite 3,3′,5′-triiodothyronine (reverse T3). The bioavailability of thyroid hormone in target tissues depends to a large extent on the supply of plasma T4 and T3, the activity of transporters mediating the cellular uptake and/or efflux of these hormones, as well as the activity of deiodinases and possibly other enzymes catalyzing their activation or inactivation. Thyroid function is regulated most importantly by the hypophyseal glycoprotein thyroid-stimulating hormone (TSH), also called thyrotropin. In turn, TSH secretion from the anterior pituitary is stimulated by the hypothalamic factor thyrotropin-releasing hormone (TRH). TSH secretion is down-regulated by negative feedback action of thyroid hormone on the hypothalamus and the pituitary. The contribution of locally produced T3 versus uptake of plasma T3 is much greater for some tissues such as the brain and the pituitary than for most other tissues. Plasma TSH is an important parameter for the diagnosis of thyroid dysfunction but is not representative for the thyroid state of all tissues. In this chapter various aspects will be discussed of: (a) the neuroendocrine regulation of thyroid function, (b) the biosynthesis of thyroid hormone (i.e. the prohormone T4), (c) the activation and inactivation of thyroid hormone in peripheral tissues, and (d) the mechanism by which T3 exerts it biological activity. A schematic overview of the hypothalamus– pituitary–thyroid–periphery axis is presented in Fig. 3.1.2.1.
Clinical assessment of the thyroid patient
Authors: Laurberg Peter , Pedersen Inge Bülow
Published: July 2011

Thyroid disorders are common, especially in older people where 10–20% may have structural abnormalities of the thyroid glan and/or thyroid function tests outside the reference range (1). Evaluation of thyroid function, size, and structure is therefore an important part of any complete history and physical examination of a patient.
Thyroid function tests and the effects of drugs
Authors: Stockigt Jim
Published: July 2011

The assessment of thyroid function by laboratory testing began in about 1934 with the measurement of oxygen consumption or basal

metabolic rate. Twenty years later measurement of protein-bound iodine became the standard technique and after a further 20 years this assay was superseded by radioimmunoassays of thyroxine (T4) and triiodothyronine (T3). Radioimmunoassays for thyroid-stimulating hormone (TSH) were reported from 1965, but early techniques could not distinguish normal values from the suppressed levels found in thyrotoxicosis. Until about 1990 this distinction was made by the administration of intravenous thyrotropin-releasing hormone (TRH), which fails to increase TSH to measurable levels in thyrotoxicosis, while producing a clear 5- to 15-fold increase in serum TSH in euthyroid subjects with normal pituitary function. Immunometric TSH assays now allow the suppressed serum TSH levels of thyrotoxicosis to be clearly distinguished from normal. This fundamental advance has coincided with the development of ingenious techniques to estimate the minute fraction of total serum T4 that circulates in the unbound state, but even the best free T4 methods offer only a marginal diagnostic advantage over the measurement of total T4, e.g. when the concentration of thyroxine-binding globulin (TBG) is abnormal. Current enthusiasm for free T4 and T3 estimation needs to be tempered by an understanding of the method-dependent limitations of these techniques, particularly in situations where assessment of thyroid function is most difficult (see below).
Nonthyroidal illness
Authors: Peeters R.P.
Published: July 2011

A few hours after the onset of acute illness, marked changes in serum thyroid hormone levels occur. This is referred to as nonthyroidal illness (NTI). The most characteristic and persistent abnormality is a low level of serum triiodothyronine (T3). Despite these low levels of serum T3, patients usually have no clinical signs of thyroid disease. Other terms for this disease state have been used, e.g. the low T3 syndrome and the euthyroid sick syndrome. In addition to nonthyroidal illness, a low T3 in euthyroid patients is seen during caloric deprivation and after the use of certain types of medication (see Chapter 3.1.4).

Low levels of thyroid hormone in hypothyroidism are associated with a decreased metabolic rate. Both in nonthyroidal illness and in fasting there is a negative energy balance in the majority of cases. Therefore the low levels of T3 during nonthyroidal illness and starvation have been interpreted as an attempt to save energy expenditure, and intervention is not required. However, this remains controversial and has been a debate for many years. In this chapter, the changes in thyroid hormone levels, the pathophysiology behind these changes, the diagnosis of intrinsic thyroid disease, and the currently available evidence whether these changes should or should not be corrected will be discussed (Box 3.1.5.1).
Thyroid imaging: nonisotopic techniques
Authors: Hegedüs Laszlo , Bennedbæk Finn N.
Published: July 2011

Clinical examination and evaluation of thyroid function remain fundamental in the evaluation of thyroid disorders, but observer variation leads to a considerable heterogeneity in the evaluation of patients with suspected thyroid disease (1). It is not surprising, therefore, that imaging of the thyroid is often performed. Although it most often cannot distinguish between benign and malignant lesions, and its clinical value is generally thought to be limited (2), a European survey demonstrated that 88% of European Thyroid Association members would use imaging in an index case of a euthyroid patient with a solitary thyroid nodule and absence of clinical suspicion of malignancy (3). In the case of a clinically benign nontoxic multinodular goitre, the figure was 91% (4).

The thyroid gland can be evaluated by several different nonisotopic imaging techniques. The most commonly used are ultrasonography, CT, and MRI. Each method has advantages and limitations, and there is no absolute clinical indication for performing any of these imaging procedures in the majority of patients. The major drawback of all techniques, in addition to expense, is that the technical advances in thyroid imaging have not been accompanied by increased specificity for tissue diagnosis. This chapter will focus on the clinical use of these methods and, as far as this is possible, compare their advantages and disadvantages (Table 3.1.6.1.1).
Environmental factors
Authors: Köhrle Josef
Published: July 2011

The hypothalamus–pituitary–thyroid–periphery (HPTP) axis has been known to be a vulnerable target for environmental factors and nutritional agents for centuries. Goitrogenesis, hypo- and hyperthyroidism, tumorigenesis, and autoimmune diseases of this gland have been linked to single or combined deficiencies of several essential trace elements. Normal thyroid function depends on adequate and balanced availability of the essential trace elements iodine, selenium, iron, and the mineral zinc in the daily diet. It has been suggested that the evolution of humankind and Eve’s route of migration out of Africa, to displace the Neanderthal people and to populate the other continents, closely followed coastlines and regions with high availability of iodine, the key element required for thyroid hormone synthesis (1, 2). Involuntary or voluntary environmental or nutritional exposure to adverse factors and agents impairing thyroid hormone synthesis, secretion, binding, transport, metabolism, and action (‘goitrogens’) contributes to the development and persistence of thyroid disorders (3). Iodine deficiency, still prevalent in many regions of our world, and iodine excess (4), both of which might occur during embryonal and fetal development as well as in newborns, adolescents, and adults, provide the platform for action of adverse agents, which might be well tolerated by a normally functioning ‘quiescent’ thyroid gland with adequate iodine supply (see Chapters 3.2.3, 3.2.4). Compounds adversely affecting the HPTP axis belong to several chemical classes of food ingredients and environmental contaminants, but might also represent pharmaceutical drugs acting either directly on biomolecules comprising the HPTP axis or after modification by phase I and/or II drug metabolism (see Table 3.2.2.1). Apart from by ingestion, several agents reach their targets after inhalation (e.g. occupational exposure or smoking) or by dermal application (e.g. UV screens).
Radiation-induced thyroid disease
Authors: Pacini Furio , Elisei Rossella , Pinchera Aldo
Published: July 2011

Radiation is a mitogen which may cause damage to the cell DNA. When sufficiently severe, the damage may result in cell death. When the damage is less severe, the consequences to the cell depend upon the gene and cell system that are affected. The thyroid gland is particularly sensitive to the effects of radiation and the evidence that radiation may damage the thyroid gland is overwhelming. Both external and internal radiation have been associated with thyroid diseases (cancer and hypothyroidism, with or without thyroid autoimmunity) both in vitro and in vivo. External radiation to the thyroid was first recognized as a cause of thyroid carcinoma in the 1950s, when cases were found in individuals who had been given radiotherapy during childhood for an enlarged thymus (1). Since then, numerous studies have confirmed and extended this initial observation.

Radioactive isotopes are used in several situations in humans. They are given in very large doses in the treatment of thyroid cancer, when the dose used is intended to kill all thyroid cancer cells, and in smaller doses in the treatment of thyrotoxicosis, with the intent to produce hypothyroidism. In these conditions the radiation doses are sufficiently high to kill the cells, thus no unwanted secondary thyroid disease occurs. Low doses of iodine isotopes are also used as tracers for diagnostic evaluation of the thyroid gland. In this situation, no cell killing is observed and there is the theoretical possibility for thyroid cell damage. However, no convincing evidence of subsequent thyroid disorders has so far been provided.

Many animal studies have shown that radio-iodine is carcinogenic to the thyroid. Some of the earlier data suggested that internal radiation by radio-iodine was less effective than external radiation, but according to one more recent study in rats (2), the carcinogenic potential of 131I and X-rays appears to be the same. In both cases, the dose–response relationship seems to be linear, indicating that low doses also carry a risk. Iodine-131 is 20–30% as effective as external X- or χ‎-rays.
Clinical assessment and systemic manifestations of thyrotoxicosis
Authors: Marcocci Claudio , Cetani Filomena , Pinchera Aldo
Published: July 2011

The term thyrotoxicosis refers to the clinical syndrome that results when the serum concentrations of free thyroxine, free triiodothyronine, or both, are high. The term hyperthyroidism is used to mean sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland; Graves’ disease is the most common example of this. Occasionally, thyrotoxicosis may be due to other causes such as destructive thyroiditis, excessive ingestion of thyroid hormones, or excessive secretion of thyroid hormones from ectopic sites; in these cases there is no overproduction of hormone by thyrocytes and, strictly speaking, no hyperthyroidism. The various causes of thyrotoxicosis are listed in Chapter 3.3.5. The clinical features depend on the severity and the duration of the disease, the age of the patient, the presence or absence of extrathyroidal manifestations, and the specific disorder producing the thyrotoxicosis. Older patients have fewer symptoms and signs of sympathetic activation, such as tremor, hyperactivity, and anxiety, and more symptoms and signs of cardiovascular dysfunction, such as atrial fibrillation and dyspnoea. Rarely a patient with ‘apathetic’ hyperthyroidism will lack almost all of the usual clinical manifestations of thyrotoxicosis (1).

Almost all organ systems in the body are affected by thyroid hormone excess, and the high levels of circulating thyroid hormones are responsible for most of the systemic effects observed in these patients (Table 3.3.1.1). However, some of the signs and symptoms prominent in Graves’ disease reflect extrathyroidal immunological processes rather than the excessive levels of thyroid hormones produced by the thyroid gland (Table 3.3.1.2).
Subclinical hyperthyroidism
Authors: Franklyn Jayne A.
Published: July 2011

Subclinical hyperthyroidism is defined biochemically as the association of a low serum thyroid-stimulating hormone (TSH) value with normal circulating concentrations of free thyroxine (T4) and free triiodothyronine (T3). The biochemical diagnosis of subclinical hyperthyroidism is dependent upon the use of sensitive assays for TSH able to distinguish normal values found in euthyroid people from reduced values, so our understanding of this topic has accumulated in recent years since such assays became widely available. An expert panel has recently classified patients with subclinical hyperthyroidism into two groups (1): (1) those with low but detectable serum TSH (0.1–0.4 mU/l) and (2) those with undetectable serum TSH (<0.1 mU/l) reflecting the fact that studies of this condition largely divide people into these categories and that the likely consequences reflect the biochemical severity of the condition.
Antithyroid drug treatment for thyrotoxicosis
Authors: Toft Anthony
Published: July 2011

The most effective and commonly used antithyroid drugs are the thionamides, including carbimazole and its active metabolite methimazole (not available in the UK). These act by inhibiting the synthesis of thyroid hormones, principally by interfering with the iodination of tyrosine by serving as preferential substrates for the iodinating intermediate of thyroid peroxidase. Oxidized iodine is thus diverted from potential iodination sites in thyroglobulin. The iodinated antithyroid drugs are desulfurated and further oxidized to inactive metabolites. There is also some evidence for an immunosuppressive action which is of doubtful clinical significance as most patients relapse after drug withdrawal. Another thionamide,

propylthiouracil, is, in addition, a potent inhibitor of type 1 outer ring deiodinase and acutely inhibits thyroxine (T4) to triiodothyronine (T3) conversion, but there is no good evidence to suggest that this effect is of any clinical relevance. Propylthiouracil tends to be reserved for those patients who have developed an adverse reaction to carbimazole or methimazole.
Surgery for thyrotoxicosis
Authors: Moreno Mauricio , Perrier Nancy D. , Clark Orlo
Published: July 2011

Surgical intervention plays a critical role in the management of thyrotoxicosis. Despite this, radioactive iodine is still the most popular treatment modality in the USA. Thyrotoxicosis, the condition of hyperthyroidism, is due to the increased secretion of thyroid hormone, and may be caused by toxic solitary nodules, toxic multinodular goitre (Plummer’s disease), or diffuse toxic goitre (Graves’ disease). Graves’ disease is the condition of goitre and associated clinical features of tachycardia and bulging eyes described by Dr Robert James Graves (1797–1853) in 1835 (1). Understanding the pathophysiology of the condition of thyrotoxicosis is essential in the appropriate selection of surgical candidates and planning the most suitable technique. Generally, accepted indications for thyroidectomy for thyrotoxicosis include: suspicion of malignancy by physical examination (firmness, irregularity, or attachment to local structures) or by fine-needle aspiration cytology of nodules; pregnancy; women desiring pregnancy within 6–12 months of treatment; lactation; medical necessity for rapid control of symptoms (patients with cardiac morbidity); local compression (pain, dysphagia); recurrence after antithyroid drug treatment; fear of radioactive iodine treatment; resistance to 131I or antithyroid drugs; or thyroid storm unresponsive to medical therapy. Other more relative indications for thyroidectomy also include: large goitres greater than 100 g that are less likely to respond to radioactive treatment and require a large treatment dose of 131I; severe Graves’ ophthalmopathy; poor compliance with antithyroid drugs; children and adolescents; a large, bothersome, and unsightly goitre; amiodarone-induced thyrotoxicosis, in cases when medical treatment is ineffective and amiodarone is necessary to treat cardiac disease; or hypersensitivity to iodine.
Management of Graves’ hyperthyroidism
Authors: Orgiazzi Jacques , Bournaud Claire
Published: July 2011

The treatment strategy for the hyperthyroidism of Graves’ disease remains a matter of controversy for several reasons. Treatment modalities available so far are symptomatic rather than pathophysiological, patients are heterogeneous in the severity and prognosis of the disease, and, in many patients, the disease is lifelong. Even symptomatic treatment should be adapted to the severity of the disease, both in terms of intensity of hyperthyroidism and degree of immunological derangement, an elusive goal so far. Current treatment modalities are medical/conservative with antithyroid drugs, often marred by relapse, and radical/destructive with radio-iodine or surgery with subsequent hypothyroidism. Being controversial, the selection of the treatment strategy also requires the patient’s informed cooperation. Finally, another peculiarity of the management of Graves’ disease is the frequent requirement of a multidisciplinary approach. This chapter will discuss general and specific therapeutic approaches of hyperthyroid Graves’ disease.
Graves’ ophthalmopathy and dermopathy
Authors: Wiersinga Wilmar M
Published: July 2011

The many and often disfiguring features of a typical patient with Graves’ ophthalmopathy are obvious at first glance (Fig. 3.3.10.1). The changed appearance of the patient has a profound effect on their emotional and social status. The various signs and symptoms can be described according to the NO SPECS classification (1) (Box 3.3.10.1). Class 1 signs can be present in any patient with thyrotoxicosis regardless of its cause. Upper eyelid retraction causes stare and lid lag on downward gaze (the latter is the well-known von Graefe’s sign). Soft tissue involvement (class 2) comprises swelling and redness of eyelids, conjunctiva, and caruncle. Symptoms are a gritty sandy sensation in the eyes, retrobulbar pressure, lacrimation, photophobia, and blurring of vision. Proptosis (class 3) can be quite marked. Upper eyelid retraction by itself may already give the impression of exophthalmos. Extraocular muscle involvement (class 4) may result in aberrant position of the globe, or fixation of the globe in extreme cases. More common is limitation of eye muscle movements in certain directions of gaze, especially in upward gaze; it is usually associated with diplopia.

Diplopia will not occur if the vision of one eye is very low (e.g. in amblyopia), or if the impairment of eye muscle motility is strictly symmetrical. Patients may correct for double vision by tilting the head, usually backwards and sideways; the ocular torticollis often leads to neck pain and headache. Corneal involvement (class 5) occurs through overexposure of the cornea due to lid lag, lid retraction, and exophthalmos, easily leading to dry eyes and keratitis. Lagophthalmos is often noted first by the patient’s partner because of incomplete closure of the eyelids during sleep. Sight loss (class 6) due to optic nerve involvement is the most serious feature, often referred to as dysthyroid optic neuropathy (DON). Besides the decrease of visual acuity, there may be loss of colour vision and visual field defects. Visual blurring may disappear after blinking (caused by alteration of the tear film on the surface of the cornea due to lacrimation or dry eyes) or after closing one eye (attributable to eye muscle imbalance). Visual blurring that persists is of great concern as it may indicate optic neuropathy (2).
Management of toxic multinodular goitre and toxic adenoma
Authors: Führer Dagmar , Lazarus John H
Published: July 2011

Toxic adenoma and toxic multinodular goitre represent the clinically important presentations of thyroid autonomy. Thyroid autonomy is a condition where thyrocytes produce thyroid hormones independently of thyrotropin (TSH) and in the absence of TSH-receptor stimulating antibodies (TSAB).

Toxic adenoma (TA) is a clinical term referring to a solitary autonomously functioning thyroid nodule. The autonomous properties of TA are best shown by radio-iodine or 99mTc imaging. The classic appearance of TA is that of circumscribed increased uptake with suppression of uptake in the surrounding extranodular thyroid tissue (‘hot’ nodule, Fig. 3.3.11.1).

Toxic multinodular goitre (TMNG) is a heterogeneous disorder characterized by the presence of autonomously functioning thyroid nodules in a goitre with or without additional nodules. These additional nodules can show normal or decreased uptake (cold nodules) on scintiscan. TMNG constitutes the most frequent form of thyroid autonomy.
Management of thyrotoxicosis without hyperthyroidism
Authors: Wiersinga Wilmar M.
Published: July 2011

Thyrotoxicosis without hyperthyroidism is a condition of thyroid hormone excess not caused by increased biosynthesis of thyroid hormones in the thyroid gland. The thyroid hormone excess in such cases originates either from the thyroid gland as a result of destructive lesions or from extrathyroidal sources. The hallmark of thyrotoxicosis without hyperthyroidism is a low uptake of radio-iodine in the neck (see Chapter 3.3.5). Cytokine-, iodine-, and amiodarone-induced thyrotoxicosis manifest themselves either as thyrotoxicosis without hyperthyroidism, or as thyrotoxicosis with hyperthyroidism in which thyroidal radio-iodine uptake is preserved. Both types are discussed in this chapter.
Subclinical hypothyroidism
Authors: Franklyn Jayne A.
Published: July 2011

Subclinical hypothyroidism is defined biochemically as the association of a raised serum thyroid-stimulating hormone (TSH) concentration with normal circulating concentrations of free thyroxine (T4) and free triiodothyronine (T3). The term subclinical hypothyroidism implies that patients should be asymptomatic, although symptoms are difficult to assess, especially in patients in whom thyroid function tests have been checked because of nonspecific complaints such as tiredness. An expert panel has recently classified individuals with subclinical hypothyroidism into two groups (1): (1) those with mildly elevated serum TSH (typically TSH in the range 4.5–10.0 mU/l) and (2) those with more marked TSH elevation (serum TSH >10.0 mU/l).
Thyroid disease during pregnancy
Authors: Lazarus John H. , Kuvera L.D. , Premawardhana E.
Published: July 2011

Thyroid disorders are common. The prevalence of hyperthyroidism is around 5/1000 in women and overt hypothyroidism about 3/1000 in women. Subclinical hypothyroidism has a prevalence in women of childbearing age in iodine-sufficient areas of between 4% and 8%. As these conditions are generally much more common in females, it is to be expected that they will appear during pregnancy. Developments in our understanding of thyroid physiology (1) and immunology (2) in pregnancy, as well as improvements in thyroid function testing (3), have highlighted the importance of recognizing and providing appropriate therapy to women with gestational thyroid disorders. Before considering the clinical entities occurring during and after pregnancy it is useful to briefly review thyroid physiology and immunology in relation to pregnancy.
Thyroid disease after pregnancy: postpartum thyroiditis
Authors: Amino Nobuyuki , Kubota Sumihisa
Published: July 2011

Postpartum thyroiditis is defined as an exacerbation of autoimmune thyroiditis during the postpartum period (1). Patients do not develop thyroid autoimmunity at the onset of postpartum thyroiditis, but have ‘subclinical autoimmune thyroiditis’ beforehand which is exacerbated after delivery. Typically an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism. However, various types of thyroid dysfunction may occur, including Graves’ disease. Therefore, any kind of thyroid dysfunction observed during the postpartum period, is referred to as ‘postpartum thyroid dysfunction’.
Thyroid disease in newborns, infants, and children
Authors: Paul van Trotsenburg A.S. , Vulsma Thomas
Published: July 2011

There are good reasons to describe congenital hypothyroidism and hyperthyroidism separately from acquired thyroid diseases because the risks of a disturbed thyroid hormone supply in young children are clearly different from the risks in older children or adults. For adequate metabolism, vertebrates with a higher degree of development, or a more complex ontogeny, are highly dependent on thyroid hormone. Nevertheless, humans appear to be able to ‘vegetate’ for years in the absence of this hormone. After resumption of hormone supply the metabolism normalizes again. However, brain development in young children does not. With the exception of the development of the neural tube, thyroid hormone is involved in regulation of later events, such as cell migration and the formation of cortical layers, and in neuronal and glial cell differentiation. Thyroid hormone also controls differentiation of not only neurons and oligodendrocytes, but also astrocytes and microglia (1).
Treatment of hypothyroidism
Authors: Toft Anthony
Published: July 2011

Treatment of primary hypothyroidism is usually both gratifying and simple and, in most cases, lifelong. Thyroxine, as l-thyroxine sodium, is the therapy of choice and is available in the UK as tablets of 25, 50, and 100 μ‎g. A greater variety of tablet strength is marketed in other parts of Europe and North America. Thyroxine has a half-life of some 7 days and should be given as a single daily dose which improves compliance. Thyroxine, taken at bedtime, is associated with higher thyroid hormone concentrations and lower thyroid-stimulating hormone (TSH) concentrations compared to the same dose taken in the morning, probably due to greater gastrointestinal uptake of thyroxine during the night (1). Omitting the occasional tablet is of no consequence and those who forget to take their medication, e.g. on vacation, will experience little in the way of symptoms for the first 2 weeks.
Management of the single thyroid nodule
Authors: Hegedüs Laszlo , Bennedbæk Finn N.
Published: July 2011

The main concern of patients and physicians alike, when dealing with the solitary thyroid nodule, is to diagnose the few cancers (approximately 5%) as rapidly and cost-effectively as possible, and to reduce superfluous thyroid surgery. Management has changed in recent years, but differences prevail as shown by an investigation among European thyroidologists (1). This chapter focuses on the palpably discrete swelling within an otherwise normal gland in the clinically and biochemically euthyroid patient (2, 3). The toxic nodule is dealt with in Chapter 3.3.11, and thyroid malignancy in Chapters 3.5.4–3.5.7.
Papillary, follicular, and anaplastic thyroid carcinoma and lymphoma
Authors: Leboulleux Sophie , Jean Schlumberger Martin
Published: July 2011

Papillary and follicular thyroid carcinomas are the most frequent forms of thyroid cancers and are among the most curable cancers. However, some patients are at high risk of recurrence or even death from their cancer, and can be identified at the time of diagnosis

using well-established prognostic indicators (1–3). The apparent increase in the incidence of thyroid carcinomas observed in recent years is mainly related to an increased detection of low risk small carcinomas in adults, which is attributed to an improvement in diagnostic techniques (4, 5). This leads to the treatment of an increasing number of low-risk patients for whom an optimal quality of life should be maintained. However, the number of high-risk patients remains unchanged and these patients require aggressive treatment and follow-up. The extent of initial treatment and follow-up should therefore be individualized according to recent guidelines and consensus (6, 7).
Medullary thyroid carcinoma
Authors: Raue Friedhelm , Frank-Raue Karin
Published: July 2011

Medullary thyroid carcinoma (MTC) is a rare calcitonin-secreting tumour of the parafollicular or C cells of the thyroid. As the C cells originate from the embryonic neural crest, MTC often have the clinical and histological features of neuroendocrine tumours. They account for 8–12% of all thyroid carcinomas and occur in both sporadic and hereditary forms (1). The majority of patients have sporadic MTC (70%), while 30% have hereditary MTC. The sex ratio in sporadic MTC is 1:1.3 (male to female), while both sexes are nearly equally affected in the familial variety (2). The highest incidence of sporadic disease occurs in the fifth decade of life, while hereditary disease can be diagnosed earlier, depending on the possibility of genetic and biochemical screening.
Child and adolescent growth
Authors: Butler Gary
Published: July 2011

The growth of a human being from a single cell to a fully mature individual is a remarkable process and something that is subject to a large number of influences across the whole growth period. Growth before birth is actually the most rapid and probably the least understood phase, but a detailed description of antenatal events is beyond this chapter. Size at birth, however, is dependent on a number of factors, primarily maternal, in particular the wellbeing of the fetoplacental unit and its level of functioning. This unit is markedly affected in maternal undernutrition, which translates into significant deleterious effects on fetal growth. Probably as important as placental function is maternal size. Small maternal size will constrain growth even when the fetus is potentially of a genetically large size. Lastly, fetal factors are important themselves. Genetic or endocrine disturbances may constrain fetal growth, but these are secondary to maternal effects.

In paediatric practice we are concerned about postnatal growth. It is useful to think of growth in three separate phases: infancy, childhood, and puberty (1). The infancy phase is largely nutrition dependent and lasts for 1–2 years. After this, the childhood phase, which is predominantly growth hormone-driven takes over, and continues until the pubertal or adolescent phase. This final phase is under the influence of the sex steroids and the speed of this phase determines the timing and rate of acceleration of the pubertal growth spurt, and the cessation of growth. It is very helpful to consider the different influences on each phase when presented with the diagnostic challenge of a child with abnormal growth (2).
Childhood endocrinology
Authors: Vliet Guy Van
Published: July 2011

Between embryonic life and the end of growth, the endocrine milieu undergoes profound changes that need to be known to understand the common paediatric endocrine disorders, to interpret results of hormone assays in newborns, infants, children, and adolescents properly, and to take advantage of some periods of life that are ‘windows of opportunity’ for some diagnoses. In this section, we will review these changes from the perspective of a practising paediatric endocrinologist. The main focus is on the ‘classical’ endocrine axes—growth hormone-releasing hormone (GHRH)/somatostatin–growth hormone–insulin-like growth factor, gonadotropin-releasing hormone–luteinizing hormone/follicle-stimulating hormone (FSH)–gonadal hormones, TRH–TSH–thyroid hormones, corticotropin-releasing factor–-adrenocorticotropin (ACTH)–adrenal steroids. Glucose and mineral metabolism will also be briefly discussed, as will childhood obesity. The increasing role of DNA-based diagnosis in paediatric endocrinology will also be highlighted.
Differential diagnosis of short stature and poor growth velocity
Authors: Johannesen Jesper , Cowell Christopher T.
Published: July 2011

Stature reflects the interaction between the genetic background of an individual and a variety of prenatal and postnatal influences including nutrition, hormones, general health, and psychological factors. Stature is a continuum ranging from tall to short individuals, the majority of those whose height is less than the 3rd centile will be representative of this normal continuum. Short individuals with a recognizable disorder are found with increasing frequency at the extremes of the population variation. The diagnostic approach to short stature will be discussed, with emphasis on the epidemiology of short stature and poor growth, the diagnoses that need to be considered, and their aetiology.
Syndromic growth disorders
Authors: Edouard Thomas , Tauber Maïthé
Published: July 2011

Short stature (SS) is defined as height less than the third percentile or below –2 standard deviation score (SDS) with reference to chronological age according to standard growth curves. Children are born small for gestational age (SGA) when their birth height and/or birth weight are below or equal to –2 SDS using standards such as Usher and McLean. In patients presenting with SS associated with abnormal physical features, malformations, or delayed development, a syndromic growth disorder should be considered. Whilst individually rare, there are many syndromes with short stature as a component—in the London Dysmorphology Database (Winter and Baraitser), there are 873 such syndromes, 175 of which are of prenatal onset. In these patients, malformations and/or sensorineural abnormalities should be systematically screened by complementary exams (skeletal X-rays, cardiac and abdominal ultrasound, complete eye and hearing evaluations). In some cases, these abnormalities could help in making the diagnosis (e.g. pulmonary stenosis suggestive of Noonan’s syndrome).

Different chromosome disorders may present with SS. For this reason, chromosome studies, preferably high-resolution analysis, should be performed to search for chromosome abnormalities in these children. Specific gene analysis may be requested when a specific syndrome is suspected. In these syndromes, growth failure may be due to a wide variety of mechanisms, including growth hormone deficiency (GHD), growth hormone resistance (Laron syndrome, bone dysplasia) or in combination with nutritional issues with, in many, the underlying mechanisms still being unknown. A complete evaluation of growth hormone/IGF-1 axis is necessary in these children.

There are many classifications of short stature, each with specific advantages and disadvantages. Indeed, syndromes with SS could be classified according to clinical presentation and in particular auxological and anthropometrical parameters (SS with normal prenatal growth, SS with intrauterine growth retardation, SS with obesity), or to pathophysiology (GHD or growth hormone insensitivity, bone disorders and idiopathic SS). Here, a classification based on clinical presentation is used. Those syndromes with SS that are most common and are often followed by paediatric endocrinologists namely Silver–Russell, Noonan’s, Turner’s and Prader–Willi syndromes will be reviewed, as well as some rarer syndromes.
The male gamete: spermatogenesis, maturation, function
Authors: Luetjens C. Marc , Weinbauer Gerhard F.
Published: July 2011

The testes fulfil two essential functions: the production and maturation of the male gametes and synthesis and the secretion of the sexual hormones. Unless otherwise specified, this chapter describes the situation in the human and provides the basis for understanding the endocrine and local regulation of testicular function. Data obtained in experimental animals are presented when the corresponding human mechanisms are not known or cannot be clarified for ethical reasons.
Endocrine and local testicular regulation
Authors: Huhtaniemi Ilpo
Published: July 2011

The testis has two functions, androgen production and spermatogenesis, and a key role in their regulation is played by the two pituitary gonadotropins, luteinizing hormone and follicle-stimulating hormone (FSH). Other hormones and growth factors also influence testicular function, often by modulating the gonadotropin effects. Moreover, a plethora of local paracrine and autocrine signals within the testis are known. The main testicular hormone, testosterone, a Leydig cell product, regulates spermatogenesis in seminiferous tubules in paracrine fashion. The other functions of testosterone are endocrine, occurring outside the testis.

This chapter summarizes the main hormonal regulatory system of the testis, the hypothalamic–pituitary–testicular axis, and how its effects are modulated by other extratesticular hormones and local testicular factors.
Testicular hormones
Authors: Huhtaniemi Ilpo
Published: July 2011

A hormone is classically considered to be a bioactive molecule that is transported via the circulation from its site of synthesis to its site of action elsewhere in the body, where it exerts its effects on specific target cells through receptor-mediated mechanisms. According to this definition, this chapter deals with the hormones produced by the testis tissue, including their synthesis, secretion, transport, mechanisms of action, and physiological functions. The testicular hormones can be classified as steroid hormones, in particular testosterone, and as peptide hormones, namely those of the activin/inhibin family. Both classes of hormones have both paracrine intratesticular and endocrine extragonadal actions, but the latter aspect of their function will be stressed here. Intratesticular functions of these molecules are discussed in Chapter 9.2.2.
Clinical appearance and examination
Authors: Nieschlag Eberhard
Published: July 2011

While infertility as such is usually not accompanied by any characteristic clinical appearance of the patient, depending on the degree of testosterone deficiency, hypogonadism leads to distinct symptoms, which—if fully expressed—can be easily recognized. Testosterone is necessary throughout life and creates identifiable phenotypical expressions in the various phases of life.

The onset of lack of testosterone can be estimated from the clinical appearance of the patient. Concerning clinical symptomatology, some androgen-determined phenotypical features require continuous androgen action (for example, beard growth, haematopoiesis, and libido), while others, once induced by testosterone, may be maintained without the continuous support of testosterone (for example, size of larynx and penis). Intrauterine lack of testosterone at the time of sexual differentiation may lead to various disorders of sexual differentiation (DSD). Postnatally, the clinical appearance of hypogonadism depends on whether the lack of testosterone becomes manifest before or after puberty (Table 9.3.1.1). While lack of testosterone before and during puberty may lead to the full picture of eunuchoidism, after regular completion of puberty its symptoms may remain relatively hidden.
Endocrine evaluation
Authors: Behre Hermann M. , Nieschlag Eberhard
Published: July 2011

The main constituent of endocrine laboratory diagnosis of testicular dysfunction is the determination of the gonadotropins, luteinizing hormone and follicle-stimulating hormone (FSH) secreted from the pituitary gland, of testosterone secreted from the Leydig cells, and of inhibin-B secreted from the Sertoli cells. Where hypothalamic or pituitary disorders are suspected as causes of testicular dysfunction, a gonadotropin-releasing hormone (GnRH) stimulation test can be performed for further differentiation. A human chorionic gonadotropin (hCG) stimulation test is done for evaluation of the endocrine reserve capacity of the testis. Additional hormone measurements are performed for special diagnostic questions, e.g. of oestradiol in cases of gynaecomastia, or hCG and oestradiol upon suspicion of a testicular tumour. Various steroid hormones, including dihydrotestosterone, androgen receptors, or androgen metabolizing enzymes (e.g. 5α‎-reductase) in the

target organs are analysed in patients with disturbances of sexual differentiation.
Testicular biopsy
Authors: Schulze Wolfgang , Knuth Ulrich A.
Published: July 2011

Testicular biopsy has been used to evaluate disturbances of male gamete production for more than 50 years, to date. In the past, opinion about its value in the clinical management of male infertility has varied considerably.
Klinefelter’s syndrome
Authors: Meschede Dieter , Nieschlag Eberhard
Published: July 2011

When in 1942 Harry Klinefelter and his colleagues described the condition carrying his name (1), its aetiology was unknown. In 1959 Jacobs and Strong (2) recognized the chromosomal basis of the disorder, until then solely defined through a set of clinical criteria. Ever since, diagnosing Klinefelter’s syndrome has required the demonstration of the 47,XXY karyotype or one of its rare variants. The occasional patient with a normal karyotype who fulfils the original clinical criteria, namely small testes, azoospermia, gynaecomastia, and elevated urinary FSH, is no longer considered as having Klinefelter’s syndrome (3). Individuals with the karyotypes 48,XXYY, 48,XXXY, and 49,XXXXY are also subsumed under the Klinefelter’s syndrome category. While these patients display all the signs and symptoms typical of the 47,XXY karyotype, they are burdened by significant additional health problems, most notably mental retardation, and malformations. For this reason, these conditions should be designated as 48,XXYY, 48,XXXY, or 49,XXXXY syndromes, respectively, and should be set apart from Klinefelter’s syndrome in the narrower sense.
XX male
Authors: Meschede Dieter , Nieschlag Eberhard
Published: July 2011

This disorder is characterized by the combination of male external genitalia, testicular differentiation of the gonads, and an apparent 46,XX karyotype. Designation of the karyotype as 46,XX is based on conventional cytogenetic analysis, where the X chromosomes have an inconspicuous appearance. If molecular methods are applied, most XX males can be shown to have translocated Y-chromosomal material on the tip of one X chromosome. Strictly speaking, the karyotype of these patients should be written as 46,X,der(X)t(Xp;Yp).

It has been suggested that this disorder be renamed ‘46,XX testicular disorder of sex development’ (1). The authors prefer to stay with the the less clumsy ‘XX male (syndrome)’.
Testicular tumours
Authors: Ståhl Olof , Eberhard Jakob , Giwercman Aleksander
Published: July 2011

Testicular cancer and the problems of male hypogonadism and infertility are closely related to each other—from a clinical as well as a biological point of view. Thus, men previously treated for testicular cancer are more and more frequently seen among patients referred to infertility clinics. This is due to the fact that:

◆ the survival rate among young testicular cancer patients is very high, being close to 95%, and the quality of life—including gonadal function—plays an important role in the men who have been cured

◆ there is an increasing knowledge that testicular function—both spermatogenesis and androgen production—in men with germ cell cancer is severely impaired. Recent research indicates a common prenatal cause of these pathologies of reproductive system

◆ modern techniques of assisted reproduction, particularly intracytoplasmic sperm injection (ICSI), have made it possible to obtain fertilization even when using ejaculates of extremely poor quality. This option has improved the possibility of cancer treated men becoming fathers. However, a source of potential worry is possible sperm DNA damage related to cancer and its treatment

◆ testicular germ cell cancer is more common in men presenting with poor semen quality. Thus, when investigating a man for infertility he should be assessed as to whether he belongs to a high-risk group for which a proper screening procedure should be offered (see below)

Apart from this clinical link between testicular cancer and male infertility, there are also some indications of common biological factors involved in aetiology and pathogenesis. In this chapter some basic biological aspects of testicular cancer will be described. In Chapter 9.5.1 the hypothesis linking a rise of gonadal malignancy and poor testicular function is explained in more detail.
Obstructions
Authors: Dondero Franco , Lombardo Francesco
Published: July 2011

Azoospermia, the absence of sperm, is the most challenging of clinical conditions despite recent progress in diagnosis and treatment. The prevalence of azoospermia is less than 1% among all men, and approximately 10–15% among infertile men. Its incidence in the general male population is 2–3% (1). Testicular (secretory) azoospermia is untreatable in most cases, and even when a cure can be attempted, success is usually low. Obstructive azoospermia, in contrast, is characterized by normal spermatogenesis and is therefore potentially treatable. Accordingly, this condition has always been the focus of physicians’ interest and attention.
Gynaecomastia
Authors: Gooren Louis J. G.
Published: July 2011

Parenchymal and stromal cells with the potential for normal breast development are equally present in prepubertal boys and girls. Men and women do not differ in sensitivity to the hormonal action of sex steroids, and therefore men have the same potential to develop breasts as women. Whether this actually occurs obviously depends on a person’s hormonal milieu. In order to understand the pathophysiology of gynaecomastia it is essential to know that breast tissue is, for its development, under control of both stimulatory hormonal action (oestrogens and progestogens) and inhibitory hormonal action of androgens. Gynaecomastia typically occurs when there is a relative dominance of oestrogenic over androgenic action; many cases of gynaecomastia are not the result of an overproduction of oestrogens per se, but rather due to the failing inhibitory action of androgens (1). In the assessment of gynaecomastia, as much attention must be paid to a potential source of feminizing hormones as to decreased androgen production or interference with the biological action of androgens.

Oestrogens stimulate the proliferation and differentiation of parenchymal ductal elements while progesterone supports alveolar development. The biological actions of oestrogens and progesterone do not appear in cases of growth hormone deficiency. Prolactin stimulates the differentiated ducts to produce milk. Testosterone inhibits the growth and differentiation of breast development, probably through an antioestrogenic action (1).

Whatever the cause, gynaecomastia shows the same histological developmental pattern. At first, there is florid ductal proliferation, with epithelial hyperplasia and increase in stromal and periductal connective tissue, with increased vascularity and periductal oedema. After approximately one year, there is increased stromal hyalinization, dilation of the ducts, and a marked reduction in epithelial proliferation, a ‘burnt-out’ phase of the condition. The result is inactive fibrotic tissue which no longer responds to endocrine therapy.

Gynaecomastia is not an uncommon finding and most cases will not represent a serious medical condition. However, gynaecomastia may signify the presence of a malignancy producing oestrogens, aromatase (the enzyme that converts androgens to oestrogens), or human chorionic gonadotrophin (hCG). Common locations of such tumours are the testis, lungs, liver or the gastrointestinal tract. Consequently, cases of gynaecomastia must be taken seriously and the diagnostic approach must reasonably rule out a malignancy in order to avoid any undue delay in its diagnosis.