bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitral Valve Disease
Authors: Maisano Francesco , Tarramasso Maurizio
Published: January 2022

Mitral valve disease involves mitral regurgitation and stenosis, respectively. Mitral regurgitation may be due to valve prolapse, papillary rupture, rheumatic disease, endocarditis, and ventricular dilatation due to heart failure with reduced ejection fraction. Diagnosis is made by echocardiography and treatment involves surgical reconstruction or surgical valve replacement, as well as the MitraclipR procedure. Mitral stenosis, on the other hand, is mainly due to rheumatic heart disease and is also diagnosed using echocardiography and treated initially medically using beta blockers, diuretics, and oral anticoagulation and, at later stages, balloon mitral valvuloplasty or mitral valve replacement.
Sympathectomy for cancer pain
Authors: Koyyalagunta Dhanalakshmi , Bhaskar Arun
Published: January 2022

Abdominal and pelvic pain in patients with malignancy can be debilitating and dramatically affects survival and quality of life. This chapter covers pain management options for abdominal and pelvic pain syndromes, including chemical neurolysis and coeliac plexus block, as well as consideration of complications and alternative approaches before concluding with some key learning points.
Spinal cord stimulation for pain caused by cancer and cancer treatment
Authors: Thomson Simon , Kruglov Dmitry
Published: January 2022

Spinal cord stimulation (SCS) has been recommended for neuropathic pain after a NICE technology appraisal 159 (TA159) and in England SCS is funded for routine specialist care; most SCSs are usually implanted for non-cancer neuropathic pain. This chapter covers considerations relevant to SCS and patient selection for SCS, as well as cancer-specific technical issues such as SCS lead positioning before concluding with a list of key learning points for the reader.
Radiofrequency brain lesioning for cancer pain
Authors: Mostofi Abteen , Pereira Erlick
Published: January 2022

Brain lesions are mainly reserved for palliation of cancer pain. They are amongst the most invasive of pain interventions with small but significant potential to cause inadvertent and irreversible neurological deficits. This chapter includes a brief discussion of the principles and practicalities of stereotactic surgery for making lesions as well as covering more specific considerations for cingulotomy and thalamotomy, before ending with a list of key learning points.
The role of high-intensity focused ultrasound in cancer pain management
Authors: Brown Matthew
Published: January 2022

This chapter will consider the use of High Intensity Focused Ultrasound (HIFU) to manage pain arising in a cancer population. This chapter covers the scientific principles underlying HIFU and the safety considerations and potential adverse events, as well as practical considerations in treatment delivery and the use of HIFU in painful conditions; the chapter concludes with a list of key learning points.
Hormones Across the Lifespan
Authors: Gibney James , Banerjee Indraneel , Ho Ken K.Y.
Published: January 2022

The endocrine system plays a central role in growth, development, metabolism, reproduction, and physical well-being throughout life. The profiles of hormones of the major pituitary axes across the lifespan are distinct, although all are subject to different configurations of feedback regulation. Fetal factors, maternal environment, and placental function shape the status and profile of each axis differently at birth. Developmental programming during life’s transitions can bring dramatic changes of pattern relationships between pituitary and target gland profiles. The hormone profiles are characterized by an orderly rhythmicity that is unique for each axis and which cannot readily be discerned from single hormone measurements. The profiles of pituitary hormones provide a key insight into regulation of the endocrine system across the human lifespan. Understanding of the attributes of each axis is critical for identifying disease and implementing appropriate treatment.
Endocrine Autoimmunity
Authors: Pearce Simon H.S. , Owen Catherine J.
Published: January 2022

The elucidation of the molecular basis for the rare monogenic polyendocrinopathy syndromes including autoimmune polyendocrinopathy type 1, has also allowed novel insights into key points of normal immune homeostasis such as thymic T-lymphocyte antigen receptor selection and the role of peripheral regulatory T cells. These fundamental advances have had far-reaching implications beyond those for endocrine patients. In contrast, the common, complex autoimmune endocrinopathies have been shown to be determined by numerous genetic variants within immune system receptors and signalling pathways along with a small number of variants in the target tissue antigens. A variety of environmental risk factors have been identified for several of these conditions, but it remains to be clarified how these impact pathogenesis at a molecular level. Moreover, the mainstay of therapies for these conditions is hormone replacement and there remains a ‘translational gap’ whereby information about disease pathogenesis has yet to be converted to useful patient advances.
Common Features of Endocrine Tumours
Authors: Jouinot Anne , Bonnet-Serrano Fidéline , Bertherat Jérôme
Published: January 2022

This chapter focuses on endocrine tumours arising from endocrine glands, as defined by the World Health Organization 2017 classification: tumours of the pituitary, the thyroid, the parathyroid, the adrenal cortex, the adrenal medulla, and extra-adrenal paraganglia, and the neuroendocrine pancreas. These tumours share specific features in terms of pathophysiology, diagnosis work-up, and clinical management. Genetic background is frequent and includes genetic predispositions to one specific tumour type, such as pituitary adenoma (AIP), primary bilateral macronodular hyperplasia (ARMC5), or pheochromocytoma/paraganglioma (SDH genes), or to multiple endocrine neoplasias (MEN1 and RET). Hormonal work-up, with basal and dynamic assays, and radiological as well as nuclear imaging based on hormone membrane receptors, are the key steps of the diagnosis process, to evaluate the amount and origin of hormonal secretion, as well as the tumour extension. Management of endocrine tumours should associate both the treatment of the tumour mass, in most cases primarily with surgery, and the control of hormone secretion.
Prevention in Endocrinology
Authors: Valabhji Jonathan , Agha-Jaffar Rochan
Published: January 2022

Changing epidemiology has led to a clear shift in focus in endocrinology disease prevention. Iodine deficiency disorders and congenital hypothyroidism were examples of conditions, which when left untreated had severe consequences including impaired neurological development. However, introduction of appropriate health policies has successfully increased early recognition and treatment, thereby reducing the associated health burden. The epidemic of type 2 diabetes has now superseded these and presents one of the greatest public health challenges. In some countries, national policies are being implemented to tackle the increasing prevalence with strategies focusing on improving the obesogenic environment, a significant modifiable contributor to type 2 diabetes, as well as strategies that aim to prevent high-risk individuals progressing through to type 2 diabetes, such as the National type 2 diabetes Prevention Programme in England. The potential for prevention in other areas including gestational diabetes, type 1 diabetes, and osteoporosis will also be explored in this chapter.
Adult Growth Hormone Deficiency
Authors: Jørgensen Jens O.L.
Published: January 2022

The best-known effect of growth hormone (GH) is stimulation of longitudinal growth in children, but GH hormone secretion continues in adulthood and exerts well-characterized metabolic effects. Growth hormone deficiency in adult hypopituitary patients (GHDA) is associated with excess morbidity and mortality from cardiovascular disease and the phenotype includes fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, and osteopaenia. Several of these features reverse and normalize with GH replacement. Known side effects are fluid retention and insulin resistance, which are reversible and dose dependent. The dose requirement declines with age and is higher in women. Epidemiological surveys show that mortality in GH replaced patients is reduced compared to untreated patients.
Prolactinomas and Hyperprolactinaemia (Including Macroprolactinaemia)
Authors: Tritos Nicholas A. , Klibanski Anne
Published: January 2022

Prolactin is secreted by pituitary lactotrophs and has an important role in reproduction and lactation. There are many causes of hyperprolactinemia, including physiologic states, medications, systemic conditions, and pituitary lesions. Prolactin-secreting pituitary adenomas (prolactinomas) represent the most common type of secreting pituitary tumours. Hyperprolactinemia may lead to central hypogonadism, infertility, and bone loss. In addition, galactorrhoea may occur, particularly in women, and gynaecomastia may occasionally develop in men. Sellar lesions associated with hyperprolactinemia may cause mass effect, including headache or visual field defects. The diagnosis of hyperprolactinemia can be made by measuring serum prolactin concentration by immunoassays. Macroprolactinaemia and the hook effect may confound the interpretation of test results. Dopamine agonist therapy represents the cornerstone of management of hyperprolactinemia and prolactinomas. Transsphenoidal pituitary surgery is generally second-line therapy for patients with prolactinomas. Radiation therapy can be recommended for patients whose tumours cannot be controlled with medical therapy and surgery.
Clinically Non-Functioning Pituitary Tumours and Gonadotropinomas
Authors: Biermasz Nienke , van Furth Wouter R.
Published: January 2022

Clinically non-functioning pituitary adenomas (NFPAs) usually present with mass effects. Transsphenoidal surgery is the cornerstone of treatment once there is an indication for decompression. In smaller NFPAs, a wait-and-scan policy is usually considered. After surgery tumour remnants are closely followed with MRI and ophthalmological evaluation. Adjuvant radiotherapy can be performed in case there is a remnant, however, given the slow growth tendency a wait and scan policy and postponing radiotherapy is an alternative approach, especially in patients with normal pituitary function. Recent years there are some innovations with respect to medical treatment. Cabergoline may help with tumour stabilization in a subset of patients and temozolomide can be attempted in aggressive forms of pituitary adenoma.
Lymphocytic Hypophysitis and other Inflammatory Conditions of the Pituitary
Authors: Molitch Mark E. , Kravarusic Jelena
Published: January 2022

Inflammatory conditions of the pituitary are very rare, and in presentation similar to adenomas by symptoms of expanding sellar mass, visual disturbances, and pituitary hormone deficiencies. They can be of various origin, autoimmune such as lymphocytic hypophysitis, secondary, as a part of immune-related adverse effects, or a part of a systemic disease such as IgG4-related disease. Due to their uncommon occurrence, pathogenesis is still largely unknown and therapies are not well established. However, as there is increase in awareness, the rate of diagnosis is increasing. This chapter outlines current knowledge on these rare conditions, approach to diagnosis with careful attention to epidemiology which often helps guide prioritization of the differential diagnosis and summarizes therapeutic approaches as they are developing.
Non-Thyroidal Illness (NTI)
Authors: Peeters Robin P. , Boelen Anita
Published: January 2022

Already a few hours after the onset of acute illness, marked changes in serum thyroid hormone levels occur. This is referred to as non-thyroidal illness (NTI) also known as the low T3 syndrome and the euthyroid sick syndrome. The most characteristic and persistent abnormality is a low serum T3. Nevertheless, patients usually have no clinical signs of thyroid dysfunction. A low T3 in euthyroid patients is also seen during caloric deprivation. Both in NTI and in fasting there is a negative energy balance in the majority of cases. Therefore, the low levels of T3 during NTI and starvation have been interpreted as an attempt to save energy expenditure, which does not need intervention. However, this remains controversial and has been a debate for many years.
Radiation-Induced Thyroid Disease
Authors: Yamashita Shunichi , Pacini Furio , Elisei Rossella
Published: January 2022

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 incidences were found in individuals who had been given radiotherapy during childhood for an enlarged thymus. This chapter takes a look at the numerous studies which have confirmed and extended these initial observations.
Autoimmune Thyroid Disease
Authors: Weetman Anthony P.
Published: January 2022

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 non-organ-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 reviews these factors and how they operate to cause Hashimoto’s thyroiditis, Graves’ disease, and related disorders. It also highlights the use of thyroid autoantibody measurement in the diagnosis of thyroid autoimmune disease.
Radioiodine Treatment of Hyperthyroidism
Authors: Luster Markus , Lassmann Michael
Published: January 2022

Radioiodine therapy was originally aimed at eliminating hyperthyroidism and thus leaving the patient euthyroid. Current strategies however established postradioiodine induction of hypothyroidism as treatment objective, thus included in the category of ‘cure’. This definition holds especially true for the management of Graves’ disease (GD) 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 the outcome of RAIT and administration of larger amounts of radioiodine have tended to make this a self-fulfilling prophecy. Although many clinicians prefer that the end result of treatment should be the more easily managed hypothyroidism, others are still reluctant to give up the therapeutic ideal of euthyroidism as the preferred result of radioiodine therapy and continue their efforts to solve the enigma of thyroid radiosensitivity.
Surgery for Thyrotoxicosis
Authors: Perrier Nancy D. , Clark Orlo H. , Fisher Sarah B.
Published: January 2022

Antithyroid medications, radioactive iodine, or thyroidectomy are viable therapeutic options for the patient with thyrotoxicosis, with relative pros and cons for each modality varying with patient comorbidities and preferences, and the expertise of the treating physicians. Of the three modalities, surgery is the most invasive but also the most definitive, and is favoured for patients with symptomatic compression, concomitant documented/suspected malignancy, or coexisting hyperparathyroidism requiring surgical intervention. Thyroidectomy for treatment of thyrotoxicosis is also advantageous for women who are pregnant, lactating, or planning pregnancy, for patients with moderate to severe Graves’ orbitopathy, or when immediate control of symptoms is necessary. In experienced hands, thyroidectomy is performed with minimal morbidity and should be considered in the patient who places more relative emphasis on prompt and definitive control of symptoms with avoidance of radioactive therapy and/or medications, with less concerns regarding operative risks and/or need for lifelong thyroid hormone replacement.
Clinical Assessment and Systemic Manifestations of Hypothyroidism
Authors: Tonacchera Massimo , Chiovato Luca
Published: January 2022

Hypothyroidism is characterized by a deficient thyroidal production of thyroid hormone. It ranges from mild cases, in which biochemical abnormalities are present, to very severe cases. This condition comprises multiple functional or structural disorders, both congenital and acquired. The clinical expression of hypothyroidism varies between individuals, depending on the cause, duration, and severity of the hypothyroid state, but almost all organs and systems may be affected. 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. This chapter describes the clinical manifestations of hypothyroidism in the adult and the peculiar clinical aspects due to different ages and aetiologies.
Causes and Laboratory Investigation of Hypothyroidism
Authors: Santini Ferruccio
Published: January 2022

Hypothyroidism is the clinical state that develops as a result of the lack of action of thyroid hormones on target tissues. Primary hypothyroidism occurs when inherited or acquired pathogenic events affect thyroid function by reducing the amount of functioning thyroid tissue or by inhibiting thyroid hormone production. Central hypothyroidism is caused by pituitary or hypothalamic abnormalities resulting in an insufficient stimulation of an otherwise normal thyroid gland. Autoimmune thyroiditis is the most common cause of spontaneous hypothyroidism in areas with adequate iodine intake. Severe environmental iodine deficiency is still crucial in the pathogenesis of hypothyroidism in some geographical areas. Permanent central hypothyroidism is rare and usually part of a disorder involving the secretion of other pituitary hormones, while transient functional abnormalities of TSH secretion are relatively common. Hormonal evaluation of hypothyroidism is mainly achieved by measurement of TSH and free thyroid hormones but additional testing may be required to achieve the proper diagnosis.
Papillary, Follicular, and Anaplastic Thyroid Carcinoma and Thyroid Lymphoma
Authors: Dobrescu Ruxandra , Badiu Corin
Published: January 2022

Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid carcinoma (DTC) is the most frequent type of thyroid cancer and generally has a good prognosis. Diagnosis is based on neck ultrasound and fine needle aspiration biopsy (FNAB) which selects patients for thyroid surgery. Total thyroidectomy is required for large, invasive tumours with lymph node invasion; lobectomy is sufficient for small nodules without any suspicious features. Clinical and pathology data are used to stratify patients according to their risk of mortality and disease recurrence. Adjuvant therapy with radioiodine is indicated in high-risk groups. Follow-up is based on serial thyroglobulin measurements and ultrasound in a dynamic risk evaluation system. In case of disease persistence or recurrence radioiodine scans, high resolution cross-sectional imaging studies with computed tomography (CT) or MRI and 18FDG-PET are performed. Particular management is required for children and during pregnancy. Anaplastic thyroid carcinoma is a rare, aggressive malignancy, affecting older patients, rapidly evolving, and almost uniformly fatal. Prompt management is essential, involving early surgery followed by external radiotherapy, chemotherapy, and palliative care when needed. Thyroid lymphoma is a rare thyroid cancer that frequently occurs on the background of autoimmune thyroiditis. Management depends on histological subtype and stage. In localized forms radiotherapy alone may be sufficient; diffuse forms require a combination of radiotherapy and chemotherapy to improve survival and decrease the risk of recurrences.
Medullary Thyroid Carcinoma
Authors: Raue Friedhelm , Frank-Raue Karin
Published: January 2022

Medullary thyroid carcinoma (MTC) is a rare calcitonin (Ctn)-secreting tumour of the C cells of the thyroid. MTC often have the clinical and histological features of neuroendocrine tumours. They account for 3–5% of all thyroid carcinomas and occur in both sporadic (70%) and hereditary forms (30%). The familial variety of MTC is inherited as an autosomal dominant trait with a high degree of penetrance and is associated with multiple endocrine neoplasia type 2 syndrome. It is caused by germline-activating mutations of the RET proto-oncogene. Detection of MTC in patients has changed in recent years with the introduction of specific strategies: Ctn screening in patients with thyroid nodules and screening with molecular methods for RET proto-oncogene mutations in patients with apparently sporadic MTC and in family members at risk for MTC. By earlier identification of patients with MTC, the presentation has changed from clinical tumours to preclinical disease, resulting in a high cure rate of affected patients with much better prognosis. Surgery represents the only curative therapeutic strategy; the definitive treatment is a total thyroidectomy and, if necessary, central and lateral lymph node dissection. Tumour staging, either postoperatively or by imaging, and measuring the tumour markers Ctn and carcinoembryonic antigen (CEA), allows for the use of a dynamic risk-adapted stratification of follow-up procedures. In advanced metastatic MTC, molecular targeted therapy using tyrosine kinase receptor inhibitors helps controlling tumour progression and prolongs progression-free survival. The outcome for most MTC patients is excellent compared to those with other cancers.
Parathyroid Anatomy, Hormone Synthesis, Secretion, Action, and Receptors
Authors: Goltzman David , Hendy Geoffrey N.
Published: January 2022

Parathyroid hormone (PTH) is produced in the parathyroid glands and is released as an 84 amino acid polypeptide whose bioactivity resides in its amino-terminal domain. PTH secretion is controlled by the parathyroid calcium-sensing receptor (CaSR), and inactivating or activating mutations in this receptor lead to inherited hypercalcaemic and hypocalcaemic disorders, respectively. PTH regulates extracellular fluid calcium homeostasis through its renal calcium-conserving action, and its bone resorbing actions. Adenomas or hyperplasia of the parathyroid glands can lead to dysregulated PTH secretion and the disorder hyperparathyroidism. Intermittently administered PTH, however, exerts a bone anabolic effect and has found use in the clinic in the treatment of osteoporosis. Both PTH (and the gene family member, parathyroid hormone-related protein or PTHrP) act through a G-protein-coupled receptor, the type 1 PTH/PTHrP receptor (PTHR1) that is widely expressed and signals through multiple second messenger pathways. Inactivating mutations in the PTHR1 cause Blomstrand’s lethal chondrodysplasia, whereas activating mutations are found in Jansen’s metaphyseal chondrodysplasia.
Familial Hypocalciuric Hypercalcaemia Types 1–3 and Neonatal Severe Primary Hyperparathyroidism
Authors: Babey Muriel , Shoback Dolores M.
Published: January 2022

The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis. The CaSR regulates parathyroid hormone (PTH) secretion and calcium reabsorption by the kidney. Loss-of-function CASR mutations on chromosome 3q21.1 cause familial hypocalciuric hypercalcaemia type 1 (FHH1). FHH1 patients are usually asymptomatic. Biochemically, FHH1 is characterized by mild-to-moderate hypercalcaemia, inappropriately low urinary calcium excretion and a normal or mildly elevated circulating PTH level. Loss-of-function GNA11 mutations on chromosome 19p13.3 lead to FHH2. GNA11 gene encodes Gα-11 which mediates downstream CaSR signalling. Patients with FHH2 mutations display a mild FHH phenotype. Loss-of-function AP2S1 mutations on chromosome 19q.13.3 give rise to FHH3. AP2S1 gene encodes the adaptor-related protein complex 2 sigma (AP2σ) which is crucial for clathrin-mediated endocytosis, CaSR signalling, and trafficking. FHH3 may be a more severe form of FHH that may produce symptomatic hypercalcaemia, low bone mineral density, and cognitive dysfunction. Calcimimetic therapy may be considered for patients with FHH types 1–3.
Hypocalcaemic Disorders, Hypoparathyroidism, and Pseudohypoparathyroidism
Authors: Hannan Fadil M. , Clarke Bart L. , Thakker Rajesh V.
Published: January 2022

Hypocalcaemia ranges from an asymptomatic biochemical abnormality to a life-threatening disorder, and may be caused by vitamin D deficiency, chronic renal failure, hypomagnesaemia, hypoparathyroidism, and pseudohypoparathyroidism. Hypoparathyroidism may occur as part of a pluriglandular autoimmune disorder or a complex congenital defect, such as the autosomal dominant DiGeorge or Hypoparathyroidism-deafness-renal anomalies (HDR) syndromes. In addition, hypoparathyroidism may occur as an isolated endocrinopathy, with autosomal dominant, autosomal recessive, and X-linked inheritances. Molecular genetic studies of hypoparathyroidism have elucidated important roles for: transcription factors (e.g. TBX1, GATA3, GCMB, and AIRE), the tubulin-specific chaperone (TBCE), and the mitochondrial genome in determining parathyroid development and function; the calcium-sensing receptor (CaSR) and G-protein subunit α-11 (Gα11) in regulating extracellular calcium and parathyroid hormone (PTH) secretion; and PTH gene expression for synthesis and secretion of PTH. Pseudohypoparathyroidism, an autosomal dominant disorder associated with PTH resistance, is due to abnormalities of Gαs, which mediates PTH1 receptor signalling.
Bones and the Kidney
Authors: Miller Paul D. , Pazianas Michael
Published: January 2022

Management of osteoporosis in patients with chronic kidney disease (CKD) is often very challenging and it should consider the pathophysiology of both disorders. Patients with stage 4–5 CKD are especially at very high risk for fragility fractures and secondary increase in mortality. Discriminating between osteoporosis and CKD-MBD is best accomplished with quantitative bone histomorphometry but biochemical markers of bone turnover, especially intact parathyroid hormone (PTH) and bone-specific alkaline phosphatase, also may be helpful. The one renal bone disease where antiresorptive osteoporosis therapies would be potentially unsafe is idiopathic renal adynamic bone disease. The two renal bone diseases where an osteoporosis pharmacological agent would not be advised are osteomalacia and primary hyperparathyroid bone disease which can be excluded by defining the underlying cause of a high bone-specific alkaline phosphatase or defining the cause of a very high intact PTH. If a stage 4–5 CKD patient with fragility fractures is felt to have osteoporosis as the major underlying metabolic bone disease causing fractures, FDA approved pharmacological agents for the treatment of osteoporosis can be beneficial on or off label.
Glucocorticoid-Induced Osteoporosis
Authors: Mazziotti Gherardo , Canalis Ernesto , Bilezikian John P.
Published: January 2022

Glucocorticoid-induced osteoporosis (GIO), the most frequent form of secondary osteoporosis, is caused by chronic exposure to glucocorticoid excess. Glucocorticoids have several direct and indirect effects on the skeleton making multifactorial the pathogenesis of GIO. Fragility fractures occur early in GIO and antiosteoporotic drugs along with calcium and vitamin D should be started soon after exposure to glucocorticoid excess. Despite several guidelines and consensus recommendations stating that patients are at a remarkably increased fracture risk, little attention is paid to this risk and guidelines are frequently not applied in real-life clinical practice. This chapter deals with the pathophysiological, clinical, and therapeutic aspects of exogenous and endogenous GIO.
Adrenal Imaging
Authors: Guest Peter
Published: January 2022

Evaluating the adrenal gland with imaging can be challenging. The adrenal glands may be morphologically within normal limits even in the presence of clear hyperfunction. Hyperplasia and small nodules may coexist. Non-functioning nodules are frequent and need to be differentiated from hyperfunctioning adenomas or malignancy. However, the high-resolution anatomical imaging provided by computed tomography (CT) and magnetic resonance imaging (MRI), together with the functional characterization afforded by radionuclide imaging, allows correlation with clinical and endocrine parameters. The use of these modalities in various adrenal disorders is detailed with illustrative images. In this chapter, the anatomy of the adrenal glands is reviewed, while imaging modalities in common modern use are described with their advantages and limitations.
Adrenal Incidentaloma
Authors: Bancos Irina , Terzolo Massimo , Arlt Wiebke
Published: January 2022

Adrenal incidentalomas are adrenal tumours discovered incidentally on around 5% of cross-sectional imaging studies performed for indications unrelated to adrenal disease. The incidental discovery of an adrenal mass has evolved into a common problem, because of the increasingly widespread use of cross-sectional imaging in current clinical practice. Over the last two decades, the number of abdominal CT and MRI imaging studies performed for various reasons quadrupled, and increasing resolution of these imaging studies allows for detection of ever smaller tumours, explaining the growing numbers of patients with adrenal incidentaloma. Any patient with a newly detected adrenal mass requires further evaluation to assess: (1) whether the adrenal mass is functioning (i.e. overproducing adrenal hormones), and (2) whether the adrenal mass is malignant or benign.
Adrenocortical Cancer
Authors: Jouinot Anne , Libè Rossella , Bertherat Jérôme
Published: January 2022

Adrenocortical cancer (ACC) is among the most aggressive endocrine tumours with an overall poor prognosis. Morbidity and mortality can be secondary to tumour-related steroid hormone excess and/or tumour growth and metastases. This potentially poor outcome explains why the early detection of adrenocortical malignancy is paramount for the investigation of adrenal masses, alongside exclusion of hormone excess. The diagnosis of adrenocortical carcinoma relies on careful investigations of clinical, endocrine, and imaging features before surgery, and histopathological examination after tumour removal. Appropriate management and follow-up by an expert multidisciplinary team is critical to improve prognosis and drive progress for this rare cancer.
Management of Phaeochromocytoma and Paraganglioma
Authors: Timmers Henri
Published: January 2022

Phaeochromocytomas and paragangliomas (PPGLs) are rare catecholamine producing tumours. The pathophysiology of PPGL is largely driven by genomic alterations. At least 35% of PPGLs occur as part of a hereditary syndrome. Catecholamine excess may lead to severe hypertension and potentially lethal cardiovascular complications. Therefore, prompt diagnosis is essential for effective treatment, usually by surgical resection. Biochemical testing should include analysis of plasma-free metanephrines or urinary fractionated metanephrines. Additional testing using the clonidine-suppression test is indicated in case of mildly elevated test results that cannot be explained by faulty sampling conditions, patient preparation, or by use of interfering medication. Following a biochemical diagnosis of PPGL, tumour localization can be achieved by CT or MRI. This chapter describes the imaging and treatment modalities that can be employed in the effective management of phaeochromocytoma and paraganglioma.
Modern Management of Congenital Adrenal Hyperplasia and Prospects for the Future
Authors: Auchus Richard J.
Published: January 2022

Congenital adrenal hyperplasia (CAH) refers to a group of genetic cortisol biosynthesis defects, with 21-hydroxylase deficiency (21OHD) being the most common form. The treatment of CAH first involves replacing the deficient hormones of adrenal and sometimes also gonadal origin. In addition, the accumulation of cortisol precursors typically leads to excess androgen and/or mineralocorticoid production. Thus, the second goal is to attenuate the production of unwanted adrenal steroids or to block their action in target tissues. Historically, the two goals were primarily accomplished with glucocorticoid therapy, both to replace the cortisol deficiency and to lower adrenocorticotropin secretion and the production of unwanted steroids. This chapter will review the principles and practical approaches to therapy for patients with CAH, focusing on the adult with 21OHD and their transition from paediatric care. The later sections will review differences in treatment strategies for other forms of CAH and potential novel therapies for the future.
Neuroendocrine Tumour Markers
Authors: Dhillo Waljit , Bech Paul
Published: January 2022

Neuroendocrine cells occur throughout the body, they are particularly prominent in the gastrointestinal tract, pancreas, C cells of the thyroid, adrenal medulla, parathyroid tissue, respiratory tract, skin, and genitourinary system. Neuroendocrine cells are characterized by the presence of dense core secretory vesicles in the cytoplasm which are used to store, process, and secrete hormones. Neuroendocrine tumours (NETs) occur in all these tissues. Due to thseir rarity, heterogeneity, varied and vague symptoms, and often slow-growing tumours, NETs can be a diagnostic challenge. Tumour biomarkers are required for diagnosis and follow-up. An ideal NET biomarker would be one that is secreted exclusively by the tumour cells and can be used for screening, prognostic indication, estimation of tumour burden, and surveillance. Although none of the currently available biomarkers completely fits this ideal, when measured in combination, they are useful for diagnosis, monitoring response to therapy and surveillance. Due to NET defective processing of pro-hormones, any new biomarker should also be able to detect these aberrant forms to increase the sensitivity of the test.
Lung Neuroendocrine Tumours
Authors: Lim Kok Haw Jonathan , Valle Juan W. , Mansoor Wasat
Published: January 2022

This chapter will focus on neuroendocrine tumours (NETs) of the lung and pancreas (panNETs) (non-functioning) summarizing the current understanding, diagnosis and management recommendations of these two subgroups NETs (functioning panNETs and other NET subtypes will be covered separately in subsequent chapters). Lung NETs are the most common subtype of NETs outside the gastroenteropancreatic (GEP) axis, and there has been an alarming rise in its incidence in recent years. Lung NETs are categorized into well-differentiated typical carcinoid (TC), well-differentiated atypical carcinoid (AC), poorly differentiated small cell lung carcinoma (SCLC) and poorly differentiated large cell neuroendocrine carcinoma (LCNEC); which has a significant implication on the treatment recommended. Meanwhile panNETs are classified morphologically into well-differentiated NETs (grades 1–3) and poorly differentiated NECs (grade 3). The majority of lung NETs and panNETs are non-functioning by virtue of absence of carcinoid syndrome and lack of positive serum neuroendocrine biomarkers. In both, histopathological, biochemical, and complete radiological work-up including the use of nuclear medicine imaging are pivotal in confirming the diagnosis. The last decade has witnessed rapid advances in systemic treatment options available for both lung NETs and panNETs with the advent of somatostatin analogues (SSAs), various targeted therapies, and chemotherapy; and also liver-directed therapies and other nuclear medicine ‘theranostics’. In view of the heterogeneity in NETs, each patient’s treatment pathway should be personalized, and it is recommended for all subtypes of NETs to be managed in high-volume centres in close partnership with a specialized multidisciplinary team.
Familial Syndromes and Genetic Causes of Paraganglioma and Phaeochromocytoma
Authors: Maher Eamonn R. , Casey Ruth T.
Published: January 2022

A phaeochromocytoma is a tumour arising from the adrenal medulla and a paraganglioma refers to its extra-adrenal counterpart, which can develop from sympathetic or parasympathetic tissue anywhere from the skull base to the pelvis. Phaeochromocytomas and paragangliomas (PPGL) are considered to be the most heritable tumours as up to 40% of patients who develop these tumours have a hereditary predisposition. This chapter provides an update on the clinical and molecular genetics of PPGL and related syndromes, as well as offering a guideline for genetic testing and surveillance of those individuals identified as carriers for a known PPGL predisposition gene.
Cowden Syndrome
Authors: Yehia Lamis , Malhotra Shreya , Eng Charis
Published: January 2022

Cowden syndrome (CS) is a multiple hamartoma syndrome characterized by high risks of benign and malignant tumours of the thyroid, breast, kidney, and endometrium, as well as neurodevelopmental disorders such as autism spectrum disorder (ASD). Affected individuals typically have macrocephaly at birth, and mucocutaneous features evident by the late 20s. The tumour suppressor gene PTEN, encoding an ubiquitously expressed phosphatase classically counteracting the PI3K/AKT/mTOR growth-promoting cascade, is the first and currently only clinically actionable CS susceptibility gene. Individuals with germline PTEN mutations have diverse phenotypes, can have different syndromic names, and fall under the umbrella term PTEN hamartoma tumour syndrome (PHTS). Ongoing investigations in the research arena are uncovering other susceptibility genes in PTEN mutation-negative patients. Clinicians play a critical role in recognizing ‘red flag’ signs and symptoms to establish a CS diagnosis. Timely diagnosis is key, as early recognition enables high-risk cancer surveillance and related medical management.
Disorders of Gonadotropin Secretion
Authors: Berga Sarah L.
Published: January 2022

Gonadal function sufficient to support gametogenesis requires appropriate gonadotropin-releasing hormone (GnRH) input to drive appropriate pituitary secretion of LH and FSH. Alterations in GnRH drive either cause or reflect gonadal dysfunction. Hypothalamic hypogonadism in men and women results from functional, theoretically reversible, reductions in GnRH drive that are linked to stress, that is, cognitions and behaviours that activate the limbic hypothalamic–pituitary–adrenal axis. Common manifestations of insufficient GnRH drive in women include anovulation and amenorrhea. Amelioration of adrenal activation has been shown to restore ovulatory ovarian function in women with functional hypothalamic amenorrhea.
Polycystic Ovary Syndrome
Authors: Chang R. Jeffrey
Published: January 2022

Polycystic ovary syndrome (PCOS) is a reproductive-metabolic disorder that is the most common endocrinopathy of women in their reproductive years of life. The reproductive phenotype includes hirsutism, irregular menstrual bleeding, and polycystic ovaries. Because of chronic anovulation, infertility is a major concern. Commonly, these features are accompanied by obesity, hyperlipidaemia, insulin resistance, and an increased risk for type 2 diabetes mellitus. In addition, there is increased prevalence of depression and anxiety disorders, acne, acanthosis nigricans, sleep apnoea, and metabolic syndrome. Genetic markers for PCOS have not been identified. The pathophysiology has been well described, but the underling basis for PCOS is unknown. The onset of symptoms occurs during or soon after puberty and there is a familial inheritance pattern. Long-term health concerns include an increased risk for uterine and cancer cardiovascular disease.
Female Hypogonadism
Authors: Yasmin Ephia , Conway Gerard S.
Published: January 2022

The natural lifespan of the ovary is occasionally interrupted by pathological processes, some known but many unknown. Premature ovarian insufficiency (POI) may be caused by genetic and chromosomal defects, autoimmune damage, and cancer treatments. POI can be a devastating diagnosis for a teenager or for someone who has yet to start a family. Knowledge of the pathogenesis of the condition, as well as treatment options in terms of hormones and assisted fertility require a multidisciplinary team comprising reproductive medicine, endocrinology, clinical psychology, and specialists in assisted conception. Premature ovarian failure is a complex condition that requires specialist services. The diagnostic work-up is aimed at determined the aetiology where possible and is followed by a screen for syndromic conditions. Oestrogen replacement and fertility options need to be reassessed at intervals and clinicians have to be vigilant for psychological sequelae.
Female Hypogonadism
Authors: Paschou Stavroula A. , Anagnostis Panagiotis , Goulis Dimitrios G.
Published: January 2022

Menopause marks the permanent cessation of menstruation and the transition to the non-reproductive stage of a woman’s life, after completion of 12 months of amenorrhoea or immediately after bilateral oophorectomy. The purpose of this chapter is to provide current knowledge regarding the different stages preceding and following the final menstrual period, the physiology of the endocrine changes occurring during the menopausal transition, the clinical manifestations, diagnosis, and differential diagnoses, as well as the pros and cons of its medical management. Hormone replacement therapy (HRT) is the treatment of choice for most. Additionally, it may be considered for osteoporosis treatment and fracture risk reduction, but only for women who present with VMS. In cases of hysterectomy, oestrogen-only formulations should be used, whereas for women with intact uterus progestogen needs to be added to counteract the harmful effects of oestrogen on the endometrium. Postmenopausal women should also be managed with lifestyle interventions, including diet, exercise, smoking cessation, and decrease in alcohol consumption, with a particular focus on bone and cardiovascular health. Alternatively, drug or non-pharmaceutical therapies may be considered for the alleviation of VMS in cases, when HRT is contraindicated. The ultimate goal of the healthcare providers should be an integrated plan for the postmenopausal women, bearing in mind that most of them will spend more than one-third of their lifespan in menopausal status.
Female Infertility and Assisted Reproduction
Authors: Balen Adam H. , Jacob Susie
Published: January 2022

Infertility is common. Female age remains the single most important factor determining the ability to conceive. General investigations address all aspects of fertility including tubal assessment, ovarian reserve, and semen analysis. Assisted conception techniques with gamete preparation enhances fertility by either bypassing absolute obstruction or boosting fecundity above that expected without treatment. Limitation of the serious complication of ovarian hyperstimulation syndrome must occur. Cryopreservation has provided a credible option for those wishing to preserve or delay fertility, with success rates equivocal with fresh treatment options. Pre-implantation genetic testing and surrogacy further widen treatment options for previously untreatable conditions. This chapters provides a brief synopsis of fertility investigation and outlines one of the main treatment options, in vitro fertilization.
Exogenous Factors and Female Reproductive Health
Authors: Lim Siew , Mousa Aya , Shorakae Soulmaz , Moran Lisa
Published: January 2022

Undernutrition adversely affects fertility. A low body weight is associated with delayed conception. When conception does occur, undernutrition could also adversely affect pregnancy outcomes. Low prepregnancy BMI (<18.5 kg/m2) is associated with increased risk of early miscarriage, preterm labour, anaemia, insufficient weight gain, and impaired intrauterine fetal growth. On the other hand, overweight and obesity are associated with increased risk of gestational diabetes, pre-eclampsia, and other complications during pregnancy and delivery. Weight loss through energy restriction, with or without exercise, improves reproductive function in overweight or obese women. Aside from body weight and energy status, maternal macronutrient, and micronutrient intakes before and during pregnancy would also influence pregnancy outcomes. Studies in mostly nutritionally at-risk women reported that balanced energy/protein supplementation (<25% energy from protein) is associated with higher birth weights but high protein supplementation (> 25% energy from protein) may increase the risk of small-for-gestational-age (SGA) infants. Reducing glycaemic index or glycaemic load of maternal diet may reduce the risk of large-for-gestational-age (LGA) births or gestational diabetes. In terms of micronutrients, current evidence supports folic acid supplementation (at least 400 µg/day) to reduce the risk of fetal abnormalities, iodine supplementation for women at risk of iodine deficiency to prevent complications in fetal physical and mental development, and iron supplementation to reduce the risk of maternal anaemia where required.
Management of Thyroid Disorders Before Assisted and Spontaneous Pregnancies
Authors: Poppe Kris , Veltri Flora , Unuane David
Published: January 2022

Severe thyroid dysfunction may lead to menstrual disorders and infertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be considered as a therapeutic option. Prior to an ART treatment, an ovarian hyperstimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating thyroid hormone supplements (LT4) before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic infertility have a higher prevalence of TAI. Women with a known hypothyroidism before pregnancy and treated with LT4 should have a serum TSH <2.5 mIU/L, both in case of assisted and spontaneous pregnancies. Women with Graves’ disease desiring pregnancy should be advised of the increased risk of maternal and fetal complications and about the possible side effects of antithyroid drugs. If necessary, pregnancy must be postponed until euthyroidism is reached and confirmed. With the exception of women planning ART or those known to have TAI, at present there are no recommendations regarding universal screening for thyroid function in the preconception phase.
Pituitary Tumours in Pregnancy
Authors: Huang Wenyu , Molitch Mark E.
Published: January 2022

Pituitary adenomas are commonly found in general population. The impact of pituitary tumour on fertility are mainly due to over-secretion and/or under-secretion of pituitary hormones due to the tumour secretion per se or compression of pituitary stalk and normal pituitary tissue by the tumour. Diagnosing and managing pituitary tumours during pregnancy are faced with many challenges, including the effect of either hormone excess or hormone deficiency on pregnancy outcome, changes in the pituitary or pituitary-related hormones during pregnancy, changes in tumour size during pregnancy, and the impact of various treatments of pituitary tumours on maternal and fetal outcomes. This chapter will discuss the diagnosis and treatment of patients with prolactinomas, acromegaly, Cushing’s disease and other pituitary tumours during pregnancy.