bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinically nonfunctioning pituitary tumours and gonadotropinomas
Authors: de Herder W. W. , Feelders R. A. , van der Lely A. J.
Published: July 2011

The significant progress that has been made in the past years in the medical treatment of all pituitary adenomas is in stark contrast with the lack of progress in the medical treatment of clinically nonfunctioning pituitary tumours, or adenomas. In fact, only secreting, or functioning, tumours can be treated by medical therapy with at least modest to very impressive effect. Clinically nonfunctioning pituitary adenomas do not produce clinical signs of hormonal hypersecretion. Therefore, signs and symptoms will depend on the mass effect of these adenomas over the central nervous system (1–3).

Due to the lack of hypersecretion of hormones, nonfunctioning pituitary adenomas present themselves because of their mass effect and compression or destruction of surrounding tissues. This could also lead to hypopituitarism, which can be the presenting symptom as well (1–3). Despite their histologically benign nature, giant and ‘invasive’ nonfunctioning pituitary adenomas are one of the most complex neurosurgical challenges. Large nonfunctioning pituitary tumours are usually confined inferiorly by the sellar dura, superiorly by the elevated sellar diaphragm, and laterally by an intact medial wall of the cavernous sinus. If the anatomical extensions of the tumour are understood and a radical tumour resection is achieved, the visual and long-term outcome can be very rewarding. The goals of surgery are twofold: first to make a pathological diagnosis, and second, because these tumours are endocrinologically silent, to decompress the neural tissue (4). The vast majority of nonfunctioning pituitary adenomas are gonadotroph cell adenomas, as demonstrated by immunocytochemistry. However, they are rarely associated with increased levels of dimeric luteinizing hormone or follicle-stimulating hormone. Increased levels of subunits (free α‎-subunit mainly, LH-B subunit more rarely), however, are more frequently encountered, but are generally modest (5).

In this chapter the term ‘clinically nonfunctioning pituitary adenomas’ is used to describe pituitary tumours, which in most instances produce low quantities of hormones causing no clinically recognizable symptomatology. In the few instances, in which such tumours produce intact gonadotropins that activate testicular or ovarian activity, the term ‘gonadotropinomas’ is used.
Thyrotropinomas
Authors: Beck-Peccoz Paolo , Persani Luca
Published: July 2011

Thyrotropinomas are rare tumours, accounting for no more than 1% of all secreting or nonsecreting pituitary adenomas (1, 2). Since the prevalence of pituitary tumours in the general population is about 0.03%, 1–3 thyrotropinomas are expected to be seen per million people. The number of reported thyrotropinomas increased exponentially in the past years, as a consequence of the introduction of ultrasensitive immunometric assays for thyroid-stimulating hormone (TSH) as first-line test for evaluating thyroid function (1). Based on the finding of measurable serum TSH levels in the presence of elevated thyroid hormone concentrations, many patients previously thought to be affected with Graves’ disease or toxic nodular goitre could be correctly diagnosed as patients with central hyperthyroidism. In our opinion, this latter term is preferable to ‘inappropriate secretion of TSH’, as it more precisely reflects the pathophysiological events underlying such an unusual disorder, where the thyroid hormone negative feedback mechanism is clearly

disrupted and TSH itself is responsible for the hyperstimulation of the thyroid gland and the consequent hypersecretion of thyroid hormones (Fig. 2.3.13.1).

Central hyperthyroidism is mainly due to autonomous TSH hypersecretion from a thyrotropinoma. However, signs and symptoms of hyperthyroidism along with biochemical findings similar to those found in thyrotropinoma, may be recorded in the minority of patients with resistance to thyroid hormones (RTH) (3, 4). This form of RTH is called pituitary RTH (PRTH), as the resistance to thyroid hormone action appears more severe at the pituitary than at the peripheral tissue level (see Fig. 2.3.13.1). The clinical importance of these rare entities is based on the diagnostic and therapeutic challenges they present. Failure to recognize these different disorders may result in undesirable consequences, such as improper thyroid ablation in patients with central hyperthyroidism or unnecessary pituitary surgery in patients with RTH. Conversely, early diagnosis and correct treatment of thyrotropinomas may prevent the occurrence of complications (visual defects by compression of the optic chiasm, hypopituitarism, etc.) and should improve the rate of cure.
Pituitary carcinoma
Authors: Ayuk John , McCabe Christopher J. , Gittoes Neil J. L.
Published: July 2011

Most pituitary adenomas are slow-growing, benign tumours. Some do, however, demonstrate aggressive growth characteristics that include infiltration of the dura, bone, and surrounding tissues. Despite such apparent aggressive features, these invasive adenomas are not considered to be truly malignant. To make a diagnosis of pituitary carcinoma requires the presence of a pituitary tumour associated with central nervous system or systemic metastases. Little is known of the pathogenesis of these tumours and the prognostication of future tumour behaviour through clinical, histopathological, or molecular analyses remains challenging (1).
Pituitary incidentalomas
Authors: Karavitaki Niki
Published: July 2011

A pituitary incidentaloma is defined strictly as a ‘totally asymptomatic nonfunctional tumour, clinically and biochemically silent, which was discovered incidentally on a patient who is asymptomatic’ or, less strictly, a pituitary mass discovered in the course of evaluation for an unrelated problem (1, 2). Based on the second definition, the term incidentaloma may not be appropriate to many of these lesions, as an incidentally detected macroadenoma may still be clinically relevant.
Hypothalamic dysfunction (hypothalamic syndromes)
Authors: Shaikh M. Guftar
Published: July 2011

The hypothalamus is a complex area of the brain and is important in co-coordinating signals between the nervous system and the endocrine system, primarily via the pituitary gland. Various processes throughout life, such as birth, puberty, and pregnancy, as well as neurological and psychiatric disorders are regulated by the hypothalamus (1). It influences many hormonal and behavioural circadian rhythms, as well as being involved in the control of body temperature, hunger, and thirst. Damage to the hypothalamus whether it is congenital or acquired will lead to significant clinical morbidity (Box 2.4.1.1). Recent advances in molecular techniques and improved neuroimaging, particularly MRI and positron emission tomography (PET) have given us a better understanding of hypothalamic syndromes and their clinical manifestations.

It may be very difficult to differentiate between hypothalamic and pituitary disease as the endocrine abnormalities are often similar. As the hypothalamus regulates both endocrine and autonomic function, there is usually a combination of endocrine and neurological disturbance in hypothalamic damage. This includes abnormal behaviour, eating disorders, and thermoregulation.

The hypothalamus consists of a number of different nuclei which have very specific functions and also secretion of hypothalamic hormones and neuropeptides (1). The clinical syndrome will depend on the location and extent of the underlying lesion. The lesion may be very small and only affect specific hypothalamic nuclei which will result in discrete symptoms; however larger lesions, which are more likely, will present with a variety of problems (Fig. 2.4.1.1). The endocrine abnormalities seen in hypothalamic syndromes usually result in pituitary hyposecretion; however due to loss of inhibitory factors hypersecretion can also occur.

Children and adolescents usually present with growth failure and disorders of puberty, which can be both delayed and precious. Adults with hypothalamic dysfunction can present with dementia, disturbances in appetite and sleep, as well as hormonal deficiencies. Causes of hypothalamic damage, particularly the anterior hypothalamus, include tumours such as craniopharyngiomas, optic nerve gliomas, and inflammatory conditions such as histiocytosis and sarcoidosis.
Pineal physiology and pathophysiology, including pineal tumours
Authors: Aulinas Anna , Colom Cristina , Webb Susan M.
Published: July 2011

The pineal gland is innervated mainly by sympathetic nerve fibres that inform the gland of the prevailing light-dark cycle and acts as a neuroendocrine transducer. The gland is located behind the third ventricle in the centre of the brain and is a highly vascular organ formed by neuroglial cells and parenchymal cells or pinealocytes. The latter synthesize melatonin as well as other indoleamines and peptides.

The main pineal hormone melatonin (N-acetyl-5-methoxytryp-tamine) exhibits an endogenous circadian rhythm, reflecting signals originating in the suprachiasmatic nucleus; environmental lighting entrains the rhythm, by altering its timing. Independently of sleep, pineal melatonin is inhibited by light and stimulated during darkness, thanks to the neural input by a multisynaptic pathway that connects the retina, through the suprachiasmatic nucleus of the hypothalamus, preganglionic neurons in the upper thoracic spinal cord and postganglionic sympathetic fibres from the superior cervical ganglia, with the pineal gland.

Melatonin deficiency may produce sleeping disorders, behavioural problems, or be associated with precocious or delayed puberty in children, while chronically elevated melatonin has been observed in some cases of hypogonadotropic hypogonadism (1, 2).
Endocrinology, sleep and circadian rhythms
Authors: Brabant G.
Published: July 2011

Endogenous circadian rhythms enable organisms to prepare for environmental changes and to temporally modify behavioural and physiological functions. A variation in energy demands appears to be the most important common denominator of these circadian changes, which renders the intimate reciprocal relation of circadian behaviour and endocrine rhythms no surprise. One of the most obvious examples of circadian behaviour is the sleep–wake cycle, closely linked to diurnal variations of locomotor activity, temperature regulation, and water/food intake. Already subtle changes in these circadian cycles may lead to detrimental effects in human biology. Such causative relationship between these changes and adverse biological effects have been obtained not only from mutations characterized in genes responsible for the generation and the integration of circadian rhythms but also from observational studies where circadian rhythmicity was experimentally changed. Life in modern societies tends to increasingly ignore the natural time cues and these environmental insults are increasingly recognized as the underlying mechanism for many pathophysiological changes and a higher susceptibility to disease. Focusing on endocrine-related effects, this chapter will highlight our current understanding of the genetic background of circadian rhythms, their integration with the light–dark cycle and their links to sleep-related changes (1).
Endocrinology of eating disorders
Authors: Krassas Gerasimos E. , Bartalena Luigi
Published: July 2011

Eating disorders affect about five million Americans every year. There are three different eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder. Eating disorders are complex conditions deriving from a complex interplay of long-standing behavioural, emotional, psychological, interpersonal, and social factors. The neuronal circuits that control the ingestion of food are mainly related to catecholaminergic, serotoninergic, and peptidergic systems. In this respect, while serotonin, dopamine and prostaglandin promote the ingestion of food, by contrast, neuropeptide Y, noradrenaline, γ‎-aminobutyric acid (GABA), and opioid peptides inhibit food ingestion, thus causing the development of eating disorders (1).

Eating disorders typically occur in adolescent girls or young women, although 5–15% of cases of anorexia nervosa and bulimia nervosa and 40% of cases of binge eating disorder occur in boys and men. Approximately 3% of young women are affected with these disorders, and probably twice that number has clinically important variants. Although early disorders mostly develop in adolescence or young adulthood, they can occur after the age of 40 years and are increasingly seen in young children (2). Eating disorders are more prevalent in industrialized societies than in nonindustrialized societies, and occur in all socioeconomic classes and major ethnic groups in the USA. About half of those who have anorexia nervosa or bulimia nervosa fully recover, approximately 30% have a partial recovery, and 20% have no substantial improvement in symptoms (2).

The aim of this chapter is to give an overview of the endocrinology of eating disorders leading to excessive weight gain or excessive weight loss in humans. It is of note that despite the strong association between obesity and eating disorders, the increase in obesity is not followed by an increase in eating disorders (3).
Genetic factors relating to the thyroid with emphasis on complex diseases
Authors: Menconi Francesca , Davies Terry F. , Tomer Yaron
Published: July 2011

The nucleus of each human cell encodes approximately 30 000 genes. A large fraction of the genes in each individual exist in a form that can vary between individuals. These variable genetic forms are termed polymorphisms, and they account for much of the normal variation in body traits, such as height and hair colour. The genetic information encoded in the DNA is stored on the chromosomes and each somatic cell contains 46 chromosomes (22 autosomes and two sex chromosomes), arranged in 23 pairs, one of each derived from each parent.

Since each individual inherits two copies of each chromosome (for autosomes), one from each parent, there are also two copies of each gene. The chromosomal location of a gene is termed the locus of the gene. When the gene in a certain locus exists in two or more forms, these variants of the gene are termed alleles. When an individual’s two alleles at a locus are identical, that individual is said to be homozygous at that locus, and when the two alleles are different, the individual is a heterozygote.

Female somatic cells contain two X chromosomes, whereas male somatic cells contain only one X chromosome. Nevertheless, the activity of genes coded for by the X chromosome is no higher in females than in males. This is due to inactivation of most of the genes on one of the two X chromosomes. Thus, in female somatic cells only one X chromosome gene is expressed, and this process of suppression is called X-chromosome inactivation. X-chromosome inactivation occurs early in embryonic life and, thereafter, in each cell either the maternal or paternal chromosome is inactivated. This results in a tissue mosaic of paternally and maternally expressed X-chromosomal alleles, with an average of 1:1 distribution. As a result, a female who is heterozygous for an X-linked gene will show a mosaic-like distribution of cells expressing either one of the two alleles. Recently X-inactivation has been postulated to play a role in autoimmune diseases and may help explain the female preponderance of autoimmune diseases (see below).
Disorders of iodine excess
Authors: Nagataki Shigenobu , Imaizumi Misa , Takamura Noboru
Published: July 2011

Iodine is an essential substrate for the biosynthesis of thyroid hormone because both thyroxine (T4) and triiodothyronine (T3) contain iodine. An adequate supply of dietary iodine is therefore necessary for the maintenance of normal thyroid function. Dietary iodine intake is increasing in many regions, especially in developed countries, mainly due to iodization of salt or bread, and it is well known that various drugs and foods contain large quantities of iodine (1), e.g. seaweeds, such as konbu (Laminaria japonica), contain

0.3% of iodine dry weight. Furthermore, large doses of iodine are used for prophylaxis against exposure to 131I. Excess iodine, as well as iodine deficiency, can induce thyroid dysfunction. The response of the thyroid gland to excess iodine and disorders due to excess iodine are the main subject of this chapter.
Autoimmune thyroid disease
Authors: Weetman Anthony P.
Published: July 2011

Along with neoplasia, autoimmunity is the most common cause of endocrine disease and, of this group of disorders, thyroid autoimmunity is the most frequent. Conversely, the autoimmune thyroid diseases are the most common organ-specific or nonorgan-specific autoimmune conditions affecting any site.

This prevalence, the ease of access to the target organ, the often slow progression of disease, and the historical legacy of being the first distinctive autoimmune process to be defined, have ensured that there is now a reasonable understanding of the main factors involved in pathogenesis. This chapter assumes a basic knowledge of immunology; readers unfamiliar with this topic can obtain further details about the fundamental processes involved in self/non-self discrimination by the immune system elsewhere (1).
Thyrotoxic storm
Authors: Klubo-Gwiezdzinska Joanna , Wartofsky Leonard
Published: July 2011

Although a rare presentation of the exaggerated manifestations of thyrotoxicosis, thyrotoxic storm is arguably the most serious complication of hyperthyroidism because of its high mortality rate. An accurate estimation of its incidence is impossible to determine because of considerable variability in the criteria for its diagnosis. The syndrome does appear to be significantly less common today than in the past, perhaps because of earlier diagnosis and treatment of thyrotoxicosis, thereby precluding its progression to the stage of crisis. Nevertheless, the syndrome may occur in 1–2% of hospital admissions for thyrotoxicosis. In such patients, it is not usually possible to distinguish those with thyrotoxic storm from those with uncomplicated thyrotoxicosis simply on the basis of routine function tests. Rather, the clinical diagnosis is based on the identification of signs and symptoms which are seen typically in thyrotoxic storm and which suggest decompensation of a number of organ systems. Some of these typical or cardinal manifestations include fever (temperature usually above 38.5°C), tachycardia out of proportion to the fever, central nervous system signs varying from confusion to apathy and even coma, and gastrointestinal dysfunction, which can include nausea, vomiting, diarrhoea, and, in severe cases, jaundice. A semiquantitative scale (Table 3.3.3.1) has been developed to aid in diagnosis (1). The earliest possible diagnosis and subsequent implementation of treatment are required to avoid a fatal outcome. Even with early diagnosis, death can occur, and reported mortality rates have ranged from 10% to 75% in hospitalized patients (1–3).
Causes and laboratory investigations of thyrotoxicosis
Authors: Latrofa Francesco , Vitti Paolo , Pinchera Aldo
Published: July 2011

The term thyrotoxicosis identifies the clinical syndrome caused by elevated circulating thyroid hormones of all sources, while the term hyperthyroidism includes only the disorders due to an increased secretion of hormones by the thyroid gland. Hyperthyroidism is the most frequent cause of thyrotoxicosis. Destructive processes involving the thyroid gland that induce unregulated discharge of preformed thyroid hormones (destructive thyrotoxicosis) and circulating thyroid hormone of extrathyroidal origin (exogenous or extrathyroidal thyrotoxicosis) are less common causes of thyrotoxicosis. Although careful history taking and physical examination often allows a diagnosis of thyrotoxicosis to be made, laboratory confirmation by measurement of thyroid-stimulating hormone (TSH) and thyroid hormone is always needed. Once thyrotoxicosis is confirmed, laboratory testing and thyroid imaging are required to identify the cause of thyrotoxicosis.
Radio-iodine treatment of hyperthyroidism
Authors: Luster Markus , Lassmann Michael
Published: July 2011

Radioactive iodine has been used successfully for almost 70 years since the first treatment took place at the Massachusetts General Hospital in Boston in 1941. However, it was not until after the Second World War that 131I became generally available for clinical applications (1). The radioactive iodine isotope is chemically identical to ‘stable’ iodine (127I) and thus becomes a part of the intrathyroidal metabolism. Its principle of action is based on the emission of β‎-rays with a range of 0.5–2 mm in the tissue leading to high local radiation absorbed doses while sparing surrounding structures. The additional γ‎-ray component of 131I allows for scintigraphic imaging of the distribution in the gland and can also be used for pre- and post-therapeutic individual dosimetry (see below).

Several therapeutic options are available for the treatment of benign thyroid disorders, namely hyperthyroidism: surgical resection (hemithyroidectomy, near-total, or total thyroidectomy), long-term antithyroid drug medication (ATD), and radio-iodine therapy (RAIT) (2, 3). These different treatment modalities are used in varying frequencies depending on geographical location, e.g. iodine supply, availability and logistics, cultural background, and patient-specific features, e.g. goitre size, presence of local symptoms, age, and hormonal status. The diversity of approaches on an international scale still remains impressive and is reflected by a great heterogeneity throughout Europe and also when compared to the USA where radio-iodine therapy is still being applied more frequently than in most European countries (4–8).

Radio-iodine therapy was originally aimed at eliminating hyperthyroidism and thus leaving the patient euthyroid. Up-to-date strategies, however, established postradio-iodine induction of hypothyroidism as the treatment objective and, thus, it is included in the category of ‘cure’. This definition holds especially true for the management of Graves’ disease when long-term hypothyroidism was the rule and stabilization of euthyroidism failed in the majority of cases. In fact, the term ‘ablation’, meaning removal or destruction, has been increasingly used to characterize radio-iodine therapy and administration of larger amounts of radio-iodine have tended to make this a self-fulfilling prophecy. Although many clinicians prefer that the end result of treatment be the more easily managed hypothyroidism, others are still reluctant to give up the therapeutic ideal of euthyroidism as the preferred result of radio-iodine therapy and continue their efforts to solve the enigma of thyroid radiosensitivity.
Clinical assessment and systemic manifestations of hypothyroidism
Authors: Tonacchera Massimo , Chiovato Luca , Pinchera Aldo
Published: July 2011

Hypothyroidism may affect people of both sexes and all ages. The clinical expression of thyroid hormone deficiency varies considerably between individuals. It is influenced mainly by the age of the patient and the rate at which hypothyroidism develops although being largely independent of its cause. Most adult patients complain of a slowing of physical and mental activity.

Hypothyroidism is a graded phenomenon, ranging from very mild cases, in which biochemical abnormalities (subclinical hypothyroidism; see Chapter 3.4.4) are present but the individual hardly notices symptoms and signs of thyroid hormone deficiency, to very severe cases in which the danger exists of sliding down into a life-threatening myxoedema coma.
Causes and laboratory investigation of hypothyroidism
Authors: Santini Ferruccio , Pinchera Aldo
Published: July 2011

Hypothyroidism is the clinical state that develops as a result of the lack of action of thyroid hormones on target tissues (1). Hypothyroidism is usually due to impaired hormone secretion by the thyroid, resulting in reduced concentrations of serum thyroxine (T4) and triiodothyronine (T3). The term primary hypothyroidism is applied to define the thyroid failure deriving from inherited or acquired causes that act directly on the thyroid gland by reducing the amount of functioning thyroid tissue or by inhibiting thyroid hormone production. The term central hypothyroidism is used when pituitary or hypothalamic abnormalities result in an insufficient stimulation of an otherwise normal thyroid gland. Both primary and central hypothyroidism may be transient, depending on the nature and the extent of the causal agent. Hypothyroidism following a minor loss of thyroid tissue can be recovered by compensatory hyperplasia of the residual gland. Similarly, hypothyroidism subsides when an exogenous inhibitor of thyroid function is removed.

Peripheral hypothyroidism may also arise as a consequence of tissue resistance to thyroid hormones due to a mutation in the thyroid hormone receptor. Resistance to thyroid hormones is a heterogeneous clinical entity with most patients appearing to be clinically euthyroid while some of them have symptoms of thyrotoxicosis and others display selected signs of hypothyroidism. The common feature is represented by pituitary resistance to thyroid hormones, leading to increased secretion of thyrotropin that in turn stimulates thyroid growth and function. The variability in clinical manifestations depends on the severity of the hormonal resistance, the relative degree of tissue hyposensitivity, and the coexistence of associated genetic defects (see Chapter 3.4.8).
Thyroid hormone resistance syndrome
Authors: Gurnell Mark , Chatterjee V. Krishna
Published: July 2011

Thyroid hormones (thyroxine T4 and triiodothyronine T3) regulate many cellular processes in virtually every type of tissue. The diverse effects of thyroid hormone include regulation of growth, control of basal metabolic rate, enhanced myocardial contractility, and functional differentiation of the central nervous system. The synthesis of thyroid hormones is controlled by hypothalamic thyrotrophin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH), and in turn, T4 and T3 regulate TRH and TSH production as part of a negative feedback loop.
Pathogenesis of nontoxic goitre
Authors: Führer Dagmar
Published: July 2011

‘Goitre’ is a clinical term defined by a thyroid enlargement above the gender- and age-specific reference range (Table 3.5.1.1). Goitre may arise from very different pathological conditions (Table 3.5.1.2) and may present with euthyroid, hyperthyroid, or hypothyroid function. On morphological grounds, a goitre may be diffuse or nodular. This chapter will focus on the pathogenesis of nontoxic goitre, also called simple or dysplastic goitre in the older literature.

Nodular goitre can be divided into solitary nodular and multinodular thyroid disease and constitutes a complex thyroid disorder with heterogeneous morphological functional and pathogenetic properties (1). Histologically, thyroid nodules are distinguished by morphological criteria according to the World Health Organization classification (2). On functional grounds, nodules are classified as either ‘cold’, ‘normal’, or ‘hot’ depending on whether they show decreased, normal, or increased uptake on scintiscan. In contrast to solitary nodular thyroid disease, which has a more uniform clinical, pathological, and molecular picture, multinodular goitre (MNG) usually comprises a mixed group of nodular entities, i.e. one usually finds a combination of hyperfunctional, hypofunctional, or normally functioning thyroid lesions within the same thyroid gland. The overall balance of functional properties of individual thyroid nodules within an MNG ultimately determines the functional status in the individual patient, which may be euthyroidism, subclinical hyperthyroidism, or overt hyperthyroidism. On the molecular level, thyroid nodules within a nodular goitre may represent polyclonal lesions or true monoclonal thyroid neoplasia.
Management of nontoxic multinodular goitre
Authors: Wiersinga Wilmar M.
Published: July 2011

Goitres can be classified according to thyroid function into toxic goitres, hypothyroid goitres, and euthyroid or nontoxic goitres (see Chapter 3.5.1). The most prevalent causes of nontoxic goitre are endemic (iodine-deficient) goitre and sporadic nontoxic goitre (diffuse or nodular). The disease entity of sporadic nontoxic goitre is defined as a benign enlargement of the thyroid gland of unknown cause, in euthyroid patients (normal serum free thyroxine (T4) and free triiodothyronine (T3) concentrations) living in an area without endemic goitre. The diagnosis is by exclusion. The prevalence of sporadic nontoxic goitre (also called simple goitre) in the adult population is high, 3.2% in the UK (see Chapter 3.1.7), and it is more common in women (5.3%) than in men (0.8%). This chapter deals predominantly with sporadic nontoxic multinodular goitre.
Genetic defects of the human somatotropic axis
Authors: Metherell Louise A. , Storr Helen L. , Savage Martin O.
Published: July 2011

Linear growth is controlled by complex interactions between genetic and environmental factors. Our understanding of the endocrine physiology of growth has been revolutionized over the last 20 years by the field of molecular genetics, which has identified many genes involved in inherited human growth disorders.

Genetic defects in the human somatotropic axis will be presented and are classified as those associated with:

◆ multiple anterior pituitary hormone deficiencies

◆ isolated growth hormone deficiency

◆ growth hormone resistance syndromes
Investigation of the slowly growing child
Authors: Patel L. , Clayton P. E.
Published: July 2011

Reduced height velocity for age and stage of puberty implies slow growth. Although this occurs independently from actual height, children identified for investigation tend to be the ones who are slowly growing, as well as short. The majority of short slowly growing children do not have a recognized endocrinopathy. The commonest growth disorders are those grouped under the heading ‘idiopathic’, which includes constitutional delay in growth and puberty, a disorder of the tempo of maturation, and familial/genetic short stature. These children present with short stature, an unremarkable phenotype, and a variable extent of growth failure. The challenge to the clinician is to differentiate these children from those who may have a defined nonendocrine pathology (for example, chronic systemic disease (Box 7.2.4.1), bone disorder, or psychosocial problem) and those who may have an abnormality within the growth hormone axis.
Growth hormone therapy for the growth-hormone deficient child
Authors: Wit Jan M. , Oostdijk Wilma
Published: July 2011

In the five decades in which growth hormone has been prescribed for children with growth hormone deficiency (GHD) there has been definite progress, but on the other hand there is still insufficient evidence to answer many basic questions. From an evidence-based perspective the present situation with respect to growth hormone treatment for GHD is therefore far from optimal. First, the diagnosis GHD cannot be defined precisely, because there is a wide range of growth hormone secretion in normally growing individuals, which overlaps with the range observed in children clinically suspected of GHD. Furthermore, all test parameters available have serious drawbacks (1). Therefore, the term GHD stands for a heterogeneous group of congenital or acquired deficiencies (or apparent deficiency). Most patients have an idiopathic isolated GHD, but particularly in that subgroup retesting at the end of growth often shows a normal stimulated growth hormone peak. Of the acquired (organic) GHD, malignancies are the most frequent aetiology, but the incidence of traumatic brain injury may be underestimated.
Growth-promoting agents for nongrowth hormone-deficient short children
Authors: Chatelain Pierre
Published: July 2011

Growth-promoting agents refer to compounds, existing naturally or otherwise, which, when given to a short child as a medication, will accelerate growth velocity (GV), bringing the child’s height closer to or within normal range. The first objective, normalizing height during the growth phase, may not normalize adult height, which is the second objective. The ideal growth-promoting agent should normalize both. The mechanism behind these two objectives is not fully understood. It seems that when the growth plate cartilage chondrocytes multiply, they also differentiate then stop multiplying. The balance between multiplication and differentiation of growth plate chondrocytes is key to normalizing final height.
Delayed puberty and hypogonadism
Authors: Fuqua John S. , Rogol Alan D.
Published: July 2011

Puberty may be defined as the physiological process resulting in the attainment of sexual maturity and reproductive capacity. Puberty is an integral component of the evaluation and treatment of endocrine disorders in children and adolescents. Not only does it impact on sexual maturation, but it has other effects with lifelong consequences, including linear growth, changes in body composition, and skeletal mineralization. Patients with disorders of puberty, including precocious and delayed puberty, make up a large percentage of the children and adolescents who consult paediatric endocrinologists. An understanding of delayed or absent puberty requires a foundation in the normal processes regulating the onset of puberty, and factors essential for its progression and completion. In this chapter, we will first review the mechanisms of normal growth and puberty, particularly with regard to their interdependence. We shall then discuss the differential diagnosis of delayed or absent puberty, and present diagnostic algorithms for hypergonadotropic and hypogonadotropic hypogonadism, emphasizing some gender-specific aspects.
Premature sexual maturation
Authors: Carel Jean-Claude , Léger Juliane
Published: July 2011

Premature sexual maturation is a frequent cause for referral in paediatric endocrinology. Although clinical evaluation will suffice to reassure the patient and family in a majority of cases, premature sexual maturation can reveal severe conditions and need a thorough evaluation to identify its cause and potential for progression, in order to propose an appropriate treatment (1). Although the use of long-acting GnRH agonists has revolutionized the treatment of central precocious puberty, questions remain regarding their optimal use (2). One of the main ongoing controversial issues in the area is the definition of normal pubertal development and there is a need for longitudinal assessments of normally developing children in the various areas of the world and of a better understanding of the factors affecting normal pubertal development to improve the recognition and proper management of premature sexual maturation.
Congenital adrenal hyperplasia in children
Authors: Riepe Felix G.
Published: July 2011

Congenital adrenal hyperplasia (CAH) is caused by the genetic impairment of one of the five enzymes required for the biosynthesis of cortisol from cholesterol. In 95% of cases 21-hydroxylase deficiency (21-OHD) is responsible for the disease (1). Classic 21-OHD has an incidence varying from 1:11 800 to 1:21 800, depending on the population background. The pathophysiology, clinical picture, genetics, and the unique aspects of management from the point of view of the paediatric endocrinologist are addressed, and the problems encountered from birth to puberty are described. The child specific issues of rare forms of CAH are summarized thereafter. The reader is referred to Chapter 5.11 for a comprehensive overview of 21-OHD and for more details on all other forms of CAH.
Late effects of cancer treatment
Authors: Toogood Andrew A.
Published: July 2011

In the last 40 years there has been a dramatic improvement in the treatment of malignant disease, particularly during childhood. The multidisciplinary approach to patient management utilizing various combinations of chemotherapeutic agents and, when appropriate, surgery, and radiotherapy has resulted in a rise in the overall survival rate from childhood cancer from 23% in the 1960s to 75% today. Acute lymphoblastic leukaemia (ALL) is cured in 81% of cases and for Hodgkin’s lymphoma and germ cell tumours cure is now achieved in excess of 90% of cases. (Fig. 7.4.1) It has been estimated that 1:715 young adults is a survivor of childhood cancer. The success seen in paediatric oncology is now being mirrored in adult oncology, particularly amongst younger adults; it is estimated that 2 million adults in the United Kingdom have been treated for and survived cancer.
Definitions and classification of disorders
Authors: Nieschlag Eberhard
Published: July 2011

The testes have a dual function: production of male gametes and synthesis of testosterone. Their loss or loss of function does not lead to a life-threatening condition, but is incompatible with procreation. The ultimate role of testosterone is to ensure the transfer of sperm to the female and thus facilitate reproduction. However, testosterone acts on practically all organs and tissues in the body, having many functions which are seemingly not aimed exclusively at reproduction. In general, testosterone is responsible for ‘ maleness’ and thus for all features of the male phenotype, metabolism, and character. Testosterone is responsible for the differences between the sexes and thus has implications ranging from biology to sociocultural aspects. In a negative sense, its actions can be studied in individuals lacking testosterone and—in a positive sense—in these individuals receiving testosterone replacement therapy. Female-to-male transsexuals under testosterone treatment may also contribute to understanding of testosterone effects.

As the dominating factor of maleness, testosterone exerts its activity throughout all phases of life. Therefore, endocrinology forms the backbone of andrology as the medical discipline dealing with male reproductive functions under physiological and pathological conditions. Andrology encompasses gonadal dysfunction in puberty, adulthood, and senescence, and deals with problems such as erectile dysfunction and male contraception. The object of andrology may be summarized as ‘ male reproductive health‘. Since a textbook of endocrinology can deal with only some, albeit important, aspects of male reproductive health, the reader is referred to specialized monographs for a more complete description of the field of andrology, e.g. Nieschlag et al . (1). In this volume, various aspects of male endocrinology are dealt with throughout, such that an integrated view of male endocrinology can only be obtained by referring to other chapters of this book. This chapter provides a classification of disorders of testicular function based on localization of cause.
Sonography
Authors: Behre Hermann M. , Nieschlag Eberhard
Published: July 2011

For diagnosis of testicular dysfunction, ultrasonography of the scrotal content has become a standard procedure in patients attending an andrology clinic (1, 2). In addition, transrectal ultrasonography of the prostate and seminal vesicles is a recommended procedure for the diagnosis of infertility and for pretreatment dia-gnosis and monitoring of testosterone therapy.
Cytogenetics and molecular genetics
Authors: Meschede Dieter , Tüttelmann Frank
Published: July 2011

Genetic aberrations are important causes of spermatogenic and endocrine testicular failure. Often, clinical skills are insufficient to demonstrate the primary genetic nature of a gonadal disorder, and cytogenetic and molecular tests should be considered for the diagnostic process (Table 9.5.3.1) (1–7). They are helpful, not only for

establishing the basic aetiology of certain types of male endocrine disturbances, but also in that karyotyping and some DNA tests have attained a pivotal role in genetic risk counselling for severely infertile couples. Also, the diagnosis of a chromosomal abnormality or single gene mutation in an infertile man can have repercussions for other members of his family. They may carry the same type of genetic aberration, and thus be at increased risk for inadvertent reproductive outcomes.

The most time-honoured method in male endocrinology is the analysis of banded metaphase chromosome preparations from blood lymphocytes, which remains of undiminished practical importance (8, 9). This technique allows for the direct visualization of the complete set of chromosomes in a somatic cell lineage and provides information on both chromosome number and structure. However, a regular karyotype in somatic cells, such as lymphocytes, does not necessarily translate into normal meiotic pairing and segregation of the chromosomes in the germ cell lineage. Meiotic cell preparations and ejaculated spermatozoa may thus be included in the diagnostic work-up of an infertile man. The place of these techniques is more in the realm of research than of daily clinical practice, as discussed below. In contrast, several molecular genetic tests are firmly established as valuable diagnostic tools. Details concerning the two most important tests, mutation analysis of the CFTR gene and screening for Y-chromosomal microdeletions, are given below.
Disturbed spermatogenesis
Authors: Rolf Claus , Nieschlag Eberhard
Published: July 2011

In general, male fertility can be assessed using semen analysis, sex hormone levels and markers of accessory glands. Additional information can be obtained by examining testicular size, and especially by ultrasonographic examination of the testes. Follicle-stimulating hormone (FSH) is the classical endocrine parameter used to discriminate between testicular impairment and obstructions of the efferent ducts; however, a complete Sertoli-cell-only syndrome (SCO syndrome) can be found even in biopsies of patients with normal FSH serum levels and normal testicular volume (1). Moreover, since testicular exploration with sperm extraction (TESE) has become a means of treating patients with azoospermia, the importance of testicular biopsies has increased. To date, it is impossible to predict with accuracy the probatility of recovering mature spermatids via TESE, or to reliably distinguish obstructive azoospermia from nonobstructive azoospermia, even with the most advanced endocrine and genetic tests. At present, testicular biopsy is a therapeutic and diagnostic procedure, in combination with testicular sperm extraction and cryopreservation of testicular sperm (Chapter 9.3.6). Indications for testicular biopsy are azoospermia, necrozoospermia or severe oligozoospermia, and suspicous intratesticular lesions noted during ultrasonographic examination (2). Techniques for appropriate histological analysis are presented in Chapter 9.3.6.
XYY male
Authors: Meschede Dieter , Nieschlag Eberhard
Published: July 2011

Men with a 47,XYY karyotype do not present with a well-defined clinical syndrome. The diagnosis relies entirely on the cytogenetic demonstration of two Y chromosomes, accompanying an otherwise normal set of chromosomes. Cases with 47,XYY/46,XY mosaicism are also subsumed under the XYY male category. The 48,XXYY karyotype is briefly discussed in Chapter 9.4.3.
Infections/inflammation of the genital tract
Authors: Dondero Franco , Lombardo Francesco
Published: July 2011

Sexually-transmitted diseases (STDs) are the primary cause of infections of the genital apparatus, and are an important cause of morbidity worldwide. These diseases diminished after the advent of antibiotics, but in the 1970s new sexual behaviour and use of non-protective contraceptive methods brought about a significant increase in genito-urinary infections, especially in young adults of fertile age. New diseases appeared alongside the classic infections syphilis, gonorrhoea, soft ulcers, venereal lymphogranuloma, and inguinal granuloma, and increased continuously in industrialised nations. Previously unknown pathogens such as Chlamydia trachomatis, genital Mycoplasma, and others came to the attention of andrologists, particularly because of often irreversible complications in the sexual and reproductive realm (1).
Immunological infertility
Authors: Dondero Franco , Gandini Loredana , Lombardo Francesco , Lenzi Andrea
Published: July 2011

Immunological infertility is the presence, in one or both partners, of an antisperm immune reaction capable of interfering with fertility variables. In about 8–10% of these couples the immunological phenomenon is on the male side, causing ‘male immunological infertility’ (1).

Since the first demonstration that a significant number of infertile men show an autoimmunity to sperm, experiments have suggested that antisperm antibodies (ASA) can interfere with the fertilizing ability of spermatozoa (2). ASA can act negatively on the motility of spermatozoa in semen, on their ability to pass through female genital secretions, or on the penetration of the oocyte. In particular, owing to in vitro fertilization techniques, it has been possible to demonstrate the effects of antibody-bound sperm directly, at the level of in vitro gamete interaction (3).

ASA can reduce the motility and concentration of spermatozoa, and can induce sperm agglutination. However, normozoospermia can be accompanied by a high percentage of antibodies bound to the sperm surface, or a high ASA titre in serum or seminal plasma. In addition, ASA can affect sperm penetration of cervical mucus. When ASA are present in cervical mucus or bound to the sperm surface, impaired sperm penetration of cervical mucus, and abnormal swimming behaviour within cervical mucus—ranging from complete immobilization of sperm, to vibratory motion with limited progression (‘shaking reaction’), to restricted tail beat frequency and loss of rotatory motion—may be observed during the post-coital test (PCT). The shaking reaction in these cases is presumably due to cross-linking of motile, antibody-coated spermatozoa to the cervical mucus gel via the Fc part of the antibody (4). ASA may also inhibit fertilization by binding specifically to membrane antigens involved in sperm–oocyte interaction. They can additionally impair the fertilization process at the levels of the acrosome reaction, of zona pellucida recognition and penetration, and of sperm–vitellus interaction (5).
Treatment of hypogonadism and infertility
Authors: Nieschlag Eberhard
Published: July 2011

Special therapeutic modalities for individual disorders, where these are available, have been mentioned in the preceding chapters. However, the therapeutic principles of hormone substitution described below apply to a number of disorders. Areas of conventional treatment of male infertility that were not described in previous chapters will also be covered here.

When dealing with infertility in men, it is also important to consider the woman. Thorough diagnosis and treatment of conditions affecting female reproductive functions are mandatory, since their optimization constitutes a substantial part of the treatment of male infertility.
Insemination, in vitro fertilization, and intracytoplasmic sperm injection
Authors: Tournaye Herman J.
Published: July 2011

Anamnesis, physical examination, and additional tests may reveal a specific cause of reproductive failure in infertile men. Whenever this is found, a specific treatment or cure should be applied. When no such treatment is available, or when specific treatment has failed, techniques of assisted reproduction may be proposed to couples suffering from long-standing male infertility. The rationale behind these is to bring the spermatozoa closer to the oocyte in an attempt to enhance the fertilization process. In recent years the role of assisted reproduction has become more important, and it has often been stated that these techniques have made clinical work-up or specific treatment of the male partner pointless.

However, this is far from true. Not only may correction of a specific dysfunction in the male avoid the use of assisted reproductive techniques, but careful work-up and treatment may also enhance the outcome of these treatments. Assisted reproductive techniques should not be viewed as a primary treatment option, but rather as a complementary treatment when other treatments have failed, or have been judged inadequate after a complete work-up.