bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenal imaging
Authors: Guest Peter
Published: July 2011

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. Nonfunctioning nodules are frequent and need to be differentiated from culpable hyperfunctioning adenomas or carcinomas. However, the increasingly sophisticated anatomical imaging provided by CT and MRI, together with the functional characterization afforded by radionuclide imaging, allows good correlation with clinical and endocrine parameters.

Embryologically, the adrenal cortex derives from coelomic mesoderm and the medulla from neural crest cells. Development is independent of the kidney and adrenal glands will normally be present in the absence of a kidney. In the newborn the adrenal glands are large structures, being one-third of the size of the kidneys. They involute rapidly, however, and in the adult are small structures. They are situated immediately above and anteromedial to the upper pole of the kidneys, although the left is less suprarenal. The right lies immediately behind the cava, alongside the right diaphragmatic crus. The left lies behind the splenic vein, lateral to the left crus.

The normal adrenal has a characteristic inverted Y- or V-shape with the two limbs fusing anteromedially. The most cranial section has a triangular appearance. Cross-sectional appearance varies according to the exact level. Each limb measures 2.5–4 cm in length and 3–6 mm in thickness. Greater than 1 cm thickness is definitely abnormal. Accessory adrenal tissue (rests) may be found in the kidney, testis, or ovary, and elsewhere in the retroperitoneum.

Arterial supply is from three sources: superior–multiple arteries from the inferior phrenic; middle from the aorta; and inferior from the renal artery. A single vein drains each adrenal. The left is a tributary of the left renal vein, the right leads directly to the cava, although rarely may join a hepatic vein first. The right adrenal vein is shorter and narrower.
Adrenal surgery
Authors: Balasubramanian Sabapathy P. , Harrison Barney J.
Published: July 2011

The indications for adrenal surgery and techniques employed have evolved significantly in the last 20 years. The need for adrenalectomy has increased due to:

◆ increased use of abdominal CT/MRI that identifies adrenal incidentalomas

◆ the more frequent biochemical diagnosis of subclinical hormonal syndromes.

The operative approach has changed with the availability of minimal access surgery; this has significant advantages for the patient in terms of reduced morbidity and faster recovery (1).

Despite these changes, the fundamental principles of adrenal surgery have remained unchanged:

◆ Biochemical investigations should be performed before localization studies and/or surgical intervention.

◆ Biopsy is rarely indicated in the investigation of adrenal lesions and is confined to confirmation of adrenal metastasis, suspected lymphoma, tuberculosis, or histoplasmosis. It should only be performed after biochemical assessment has excluded phaeochromocytoma.

◆ Close collaboration with colleagues in endocrinology, biochemistry, and radiology is essential for good outcomes.

This chapter will focus on the surgical aspects of treatment. The pathology of adrenal disease, details of biochemical and radiological investigations, and the nonsurgical modalities of treatment are covered elsewhere.
Primary aldosteronism and other steroid-related causes of endocrine hypertension
Authors: Connell John M.C. , Freel E. Marie
Published: July 2011

Mineralocorticoid hypertension is characterized by increased distal renal tubular sodium reabsorption, raised body sodium content, plasma volume expansion, markedly reduced body potassium content, with a metabolic alkalosis and suppression of renin production by the juxtaglomerular cells of the kidney (and correspondingly low levels of angiotensin II). Primary aldosteronism is the most common cause of mineralocorticoid hypertension (1); less frequent causes include the rare inborn errors of adrenal steroid synthesis (11β‎-hydroxylase and 17α‎-hydroxylase deficiency), alterations in corticosteroid metabolism (syndrome of apparent mineralocorticoid excess), and constitutive activation of the epithelial sodium channel (Liddle’s syndrome).
Cushing’s syndrome
Authors: Newell-Price John
Published: July 2011

Harvey Cushing described the first case of Cushing’s syndrome with a severe phenotype in 1912. Since that time, investigation and management of Cushing’s syndrome has remained a significant clinical challenge (1, 2) and patients suspected of this diagnosis warrant referral to major centres.

Endogenous Cushing’s syndrome is due the chronic, excessive, and inappropriate secretion of cortisol. When presentation is florid diagnosis is usually straightforward, but in modern practice Cushing’s syndrome is frequently and increasingly considered in mild cases in the absence of the classical signs in the context of osteoporosis, diabetes, hypertension, gynaecology, and psychiatric clinics, and achieving a diagnosis can be difficult. Appropriate management of Cushing’s syndrome is dependent on correctly identifying the cause of excess cortisol. Separating non-ACTH-dependent causes (adrenal tumours) from ACTH-dependent causes (pituitary or ectopic secretion of ACTH) is usually simple. However, many ectopic sources are occult and the differentiation of the source of ACTH secretion may require meticulous and repeated investigation to enable the appropriate surgery to be undertaken.

In most circumstances the mainstay of therapy remains surgery to either an ACTH-secreting tumour or directly to the adrenal glands, but additional treatment with cortisol-lowering drugs and tumour-directed radiotherapy is often needed.
Adrenal insufficiency
Authors: Arlt Wiebke
Published: July 2011

In 1855, Thomas Addison identified a clinical syndrome characterized by wasting and hyperpigmentation as the result of adrenal gland destruction (1). This landmark observation paved the way for progress in understanding and treating adrenal insufficiency, with the introduction of adrenal extracts for treatment of Addison’s disease by the groups of Hartman and Pfiffner in 1929. However, long-term survival of patients with adrenal insufficiency only became possible after the seminal work of Edward Kendall, Philip Hench, and Tadeus Reichstein on the characterization and therapeutic use of cortisone. In 1946, Lewis Sarrett, a Merck scientist, achieved a partial synthesis of cortisone, which marked the beginning of industrial-scale production of cortisone. In 1948, in a fundamental clinical experiment at the Mayo Clinic, the first patient with Addison’s received intravenous injections of Kendall’s Compound E, cortisone, resulting in ‘notable improvement of his condition’. This was followed by the groundbreaking trials on the use of cortisone in rheumatoid arthritis yielding unanticipated clinical improvements, which quickly led to the labelling of cortisone as ‘the wonder drug’. In November 1950, cortisone was made available to all physicians in the USA, a rapid translational development process, which culminated in the award of the 1950 Nobel Prize in Medicine to Kendall, Hench, and Reichstein. This progress reached other countries with variable delay and widespread availability of cortisone in the UK was achieved by joint efforts of Glaxo and the Medical Research Council. Though almost 150 years have passed since Addison’s landmark observations and 60 years since the introduction of life-saving cortisone, there are still advances and challenges in the management of adrenal insufficiency, summarized in this chapter.
VIPomas
Authors: Wynne Katie
Published: July 2011

Vasoactive intestinal polypeptide (VIP) secreting tumours are rare neuroendocrine tumours. The associated syndrome was first described by Priest and Alexander in 1957. They reported a case that they thought to be a variant of the Zollinger–Ellison syndrome—a patient with an islet cell tumour associated with diarrhoea, peptic ulceration, and hypokalaemia (1). The following year, Verner and Morrison described a syndrome of profuse, refractory, watery diarrhoea with severe hypokalaemia and dehydration associated with a non-β‎-cell islet cell tumour (2). Historical terms for this syndrome have included ‘pancreatic cholera’ (as the diarrhoea is similar to the secretory diarrhoea observed in cholera) and the acronym WDHA (watery diarrhoea, hypokalaemia, and achlorhydria). However, these terms are inaccurate descriptions of a syndrome that can be associated with both extrapancreatic tumours and normal gastric acid secretion. In 1973, Bloom first connected the watery diarrhoea with an elevated plasma VIP level and an increased tumour content of VIP, suggesting the term ‘VIPoma syndrome’ (3). There followed a debate as to whether VIP was a marker for the syndrome or the causative agent for the diarrhoea. However, in 1983, Kane infused porcine VIP intravenously in healthy human subjects, achieving VIP levels similar to patients with VIPomas. Profuse watery diarrhoea developed within 4 h of infusion, providing evidence that VIP was indeed the mediator of the syndrome (4).
Imaging neuroendocrine tumours of the gastrointestinal tract
Authors: Jackson James E. , Roddie Mary E.
Published: July 2011

Gastroenteropancreatic (GEP) tumours are best divided into two distinct groups when discussing their radiological imaging. First are the functioning insulinomas and gastrinomas, which are often small at presentation; imaging of these lesions is usually aimed at localization of the primary tumour (and exclusion of metastatic disease) with a view to surgical excision. Second are the nonfunctioning neoplasms and the functioning tumours—carcinoids being the most common—which secrete a variety of other hormones including glucagon, vasoactive intestinal polypeptide, 5-hydroxytryptamine, somatostatin, serotonin, and pancreatic polypeptide. These are often large at presentation and are, therefore, obvious on cross-sectional imaging studies or have already metastasized; the role of the radiologist in this group is usually that of documenting the extent of disease to guide operative or nonoperative therapy. These two groups will be discussed separately.
Multiple endocrine neoplasia type 2
Authors: Martin Niamh M. , Meeran Karim , Bloom Stephen R.
Published: July 2011

Multiple endocrine neoplasia type 2 (MEN 2) is a rare cancer susceptibility syndrome which has at least three distinct variants: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The syndrome was first described by John Sipple in 1961 (1). The features of MEN 2A and its clinical variants are outlined in Box 6.12.1. Medullary thyroid carcinoma (MTC) is seen in all variants of MEN 2A and is frequently the earliest neoplastic manifestation, reflecting its earlier and overall higher penetrance. MEN 2 is due to the autosomal dominant inheritance of a germline missense mutation in the ‘hot-spot’ regions of the rearranged during transfection (RET) (OMIM 164761) proto-oncogene (2, 3). MEN 2 has an estimated prevalence of 1:30 000, with MEN 2A accounting for more than 75% of cases. The introduction of RET screening in family members of affected individuals has significantly altered the clinical outcome of MEN 2, by allowing prophylactic surgery for MTC, and screening enabling early intervention for phaeochromocytoma (4, 5). Prior to the availability of genetic screening, more that half of MEN 2 affected individuals died before or during the fifth decade from metastatic MTC or cardiovascular complications from an underlying phaeochromocytoma.
von Hippel–Lindau disease and succinate dehydrogenase subunit (SDHB, SDHC, and SDHD) genes
Authors: Maher Eamonn R.
Published: July 2011

This chapter considers the clinical and molecular features of von Hippel–Lindau (VHL) disease (OMIM 193300) and mutations in succinate dehydrogenase subunit genes (SDHB (OMIM 115310), SDHC (OMIM 605373), and SDHD (OMIM 168000)). Both disorders are important causes of phaeochromocytoma and, in addition to having overlapping clinical phenotypes, also share some similarities in mechanisms of tumourigenesis.
Carney’s complex
Authors: Stratakis Constantine A.
Published: July 2011

Carney’s complex (CNC) is an autosomal dominant disorder, which was described in 1985 as ‘the complex of myxomas, spotty pigmentation, and endocrine overactivity’ in 40 patients (1). Since then, more than 500 index cases have been reported, resulting in better definition of the disease and the establishment of diagnostic criteria (2, 3). As implied from the initial description, CNC is not only a multiple neoplasia syndrome, but also causes a variety of pigmented lesions of the skin and mucosae. (4) Several patients described in earlier years under the acronyms NAME (nevi, atrial myxomas, and ephelides) and LAMB (lentigines, atrial myxomas, and blue nevi) probably had CNC (5, 6). Thus, lentigines, blue nevi, café-au-lait spots, and cutaneous tumours, such as myxomas, fibromas, and others, are major features of the disease (4, 7–10).

The clinical characteristics of CNC have been reviewed and are presented in Box 6.15.1 (2, 9). A definite diagnosis of CNC is given if two or more major manifestations are present (4, 9, 11, 12). A number of related manifestations may accompany or suggest the presence of CNC but are not considered diagnostic of the disease (Box 6.15.1). Cutaneous manifestations constitute three of the major disease manifestations: (1) spotty skin pigmentation with a typical distribution (lips, conjunctiva, and inner or outer canthi, genital mucosa); (2) cutaneous or mucosal myxoma; and (3) blue nevi (multiple) or epithelioid blue nevus. Suggestive or associated with CNC findings but not diagnostic are: (1) intense freckling (without darkly pigmented spots or typical distribution); (2) multiple blue nevi of common type; (3) café-au-lait spots or other ‘birthmarks’; and (4) multiple skin tags or other skin lesions, including lipomas and angiofibromas.

The relationship between the cutaneous and noncutaneous manifestations of CNC appears to be an essential clue to the molecular aetiology of the disease. According to the latest reports, more than half of CNC patients present with both characteristic dermatological and endocrine signs; however, a significant number of patients present with skin lesions that are only ‘suggestive’ and not characteristic of CNC (9). A recent classification based on both dermatological and endocrine markers has subgrouped CNC patients as: multisymptomatic (with extensive endocrine and skin signs); intermediate (with few dermatological and endocrine manifestations); and, paucisymptomatic (with isolated primary pigmented nodular adrenocortical disease (PPNAD) alone and no cutaneous signs) (9).
Molecular and clinical characteristics of the McCune–Albright syndrome
Authors: Lietman Steven A. , Levine Michael A.
Published: July 2011

Heterotrimeric guanine nucleotide-binding proteins (G proteins) couple extracellular receptor proteins to intracellular effector enzymes and ion channels. The observation that alterations in G protein-coupled signalling pathways can impact cellular function and proliferation, and cause human disease, has stimulated investigation into the molecular and pharmacological regulation of G protein expression and action. The most well characterized models for altered G protein expression defects have been based on naturally occurring mutations in GNAS, a complex gene at 20q13 which encodes the α‎ subunit of Gs, the G protein that stimulates adenylyl cyclase. Somatic mutations in GNAS (OMIM 139320) that activate Gα‎s are present in a subset of endocrine tumours and in patients with the McCune–Albright syndrome (OMIM 174800), a sporadic disorder characterized by increased hormone production and/or cellular proliferation of many tissues. By contrast, germline mutations of the GNAS gene that decrease expression or function of Gα‎s are present in subjects with Albright’s hereditary osteodystrophy (AHO), a heritable disorder associated with a constellation of developmental defects and, in many patients, reduced responsiveness to multiple hormones that signal through receptors that require Gα‎s to activate adenylyl cyclase EC 4.6.1.1 (i.e. pseudohypoparathyroidism type 1a (OMIM 103580)). McCune–Albright syndrome (MAS) and AHO represent contrasting gain of function and loss of function mutations in the GNAS gene, respectively. Clinical and biochemical analyses of subjects with these syndromes have extended our understanding of the developmental and functional consequences of dysfunctional G protein action, and have provided unexpected insights into the importance of cAMP as a regulator of the growth and/or function of many tissues. This chapter will focus on the clinical implications of activating mutations of GNAS as the basis for MAS.
Cowden’s syndrome
Authors: Eng Charis
Published: July 2011

Cowden’s syndrome (OMIM 158350), named after Rachel Cowden, is an autosomal dominant inherited cancer syndrome characterized by multiple hamartomas involving organ systems derived from all three germ cell layers and a risk of breast and thyroid cancers (1, 2). Endocrinologists may make the diagnosis of Cowden’s syndrome when they are presented with these patients’ endocrine lesions, chief of which are multinodular goitre, thyroid adenomas, and epithelial thyroid cancer. The Cowden’s syndrome susceptibility gene, PTEN, is located on chromosome sub-band 10q23.3 (3, 4).
The generation and use of human embryonic stem cells
Authors: Englund Mikael C. O. , Barratt Christopher L. R.
Published: July 2011

Ever since the first human embryonic stem cells (hES) were successfully derived and propagated in 1998 (1), an obvious topic of discussion has been the development of novel therapies based on stem cell technology for a number of diseases and conditions. Targets could include type 1 diabetes, Alzheimer’s disease, spinal cord injury, and Parkinson’s disease to name a few. hES cells can also be used for tissue engineering, to replace for example bone and cartilage, and for drug discovery. Exciting proof of principal experiments in animals demonstrate the clinical potential in this field. For example, in a rat model of Parkinson’s disease, dopamine neural grafts derived from mouse Es cells showed long-term survival, the production of dopamine and, importantly, persistent improvements in movement behaviour (2). The promises of these potential treatments is enormous. However, there are many hurdles to overcome before a therapy based on stem cells is a clinical reality. We outline (A) the variety of methods to derive hES cells including somatic cell nuclear transfer (SCNT) and describe the challenges and possible avenues of further use; (B) discuss the development of clinical grade hES cells and their use in the drug discovery process; and (C) alternative strategies to patient specific therapy including induced adult pluripotent stem cells (iPS cells).
Hormonal contraception
Authors: Kaneshiro Bliss , Edelman Alison
Published: July 2011

The first widely available hormonal contraceptive method, the birth control pill, was first introduced in the 1960s. It was both a response to, and a reflection of, the societal and philosophical currents of the time. The idea that fertility could be controlled, pregnancy planned, and population stabilized to decrease poverty, manifested reason and rationalism, as well as the concept that science could be used to improve life. Indeed, the increased utilization of various hormonal contraceptive methods over the last four decades is now regarded as one of the most successful public health ventures of our time. Money spent on family planning services has been estimated to result in more than triple the savings in prenatal and neonatal costs (1).

Although it is now viewed as one of the great inventions of the 20th century, hormonal contraception has also been controversial. It allowed for the separation of sex from pregnancy and reproduction, and is cited by many as a catalyst to the sexual revolution. Consequently, hormonal contraceptives have been some of the best studied and closely scrutinized medications in history.

Hormonal contraceptives can be divided into two major categories, the progestin-only methods and combined hormonal contraception, which contains an oestrogen and progestin component. With all hormonal contraceptives, the progestin component has the dominant hormonal effect. The progestin component is also responsible for the mechanism of contraceptive action with the oestrogen component of the combined methods serving mainly to regulate bleeding (2). The combined hormonal methods have been constituted in the form of a pill, injection, transdermal patch, and ring. Progestin-only methods have been formulated to be delivered in the form of a pill, injection, subdermal implant, and intrauterine device (IUD).

Overall, hormonal contraception has been shown to be remarkably safe, especially when compared with pregnancy, which is one of the most medically-threatening times in a woman’s life.

The World Health Organization (WHO) has published evidence-based guidelines to help assist in contraceptive decision-making. The WHO Medical Eligibility Criteria utilizes a grading system to provide information about the safety of a particular method in women with medical conditions (1 = no restrictions for use; 2 = the advantages generally outweigh the risks; 3 = the risks outweigh the benefits; 4 = the risk is unacceptable). This grading system is based on an extensive review of the literature, as well as expert consensus statements (3).
Premenstrual syndrome
Authors: Rapkin Andrea , Zapata Mya
Published: July 2011

The premenstrual disorders, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are psychoneuroendocrine disorders characterized by a constellation of affective, somatic, and behavioural symptoms that occur monthly, during the luteal phase of the menstrual cycle with relief soon after the onset of menses. PMS affects approximately 15–40% of reproductive aged women depending on criteria for diagnosis. PMDD is a severe form of PMS, with an emphasis on the affective symptoms. It has been estimated that only 5–8% of women meet the strict criteria for PMDD, but up to 20% may be one symptom short of meeting the criteria (1). The premenstrual syndromes adversely impact relationships, activities of daily living, and workplace productivity.

The research and treatment of the premenstrual disorders have been hampered by lack of consensus regarding the specific diagnostic criteria, methods of assessment of symptoms and impairment, and absence of animal models or biological markers for the disorders. However, elucidation of various aspects of the pathophysiology, well designed multicentre treatment trials, and patient and clinician education have successfully improved diagnosis and management This chapter will review symptoms, definitions, diagnostic criteria, aetiology, evaluation, and nonpharmacological and pharmacological management of PMS and PMDD.
Primary ovarian failure
Authors: Conway Gerard S. , Doyle Jacqueline , Melanie Melanie C.
Published: July 2011

The average age of menopause, denoted by the last menstrual period, occurs at an average age of 50.7 years in the western world (1) and this age has been found to be constant across generations, although one group have reported a secular trend to advancing menopausal age (2). The age of menopause in an individual is determined by both genetic and environmental factors (1, 3). Menopause before the age of 40 is most commonly taken to be the definition of ‘premature ovarian failure’ and this coincides approximately with youngest one percent of the frequency distribution of the age of menopause (Fig. 8.1.5.1). For every decade before 40 the prevalence of POF is estimated to decrease by a factor of 10.

Thus, in presence of normal karyotype, 1:1000 of women at 30 has POF, 1:10 000 at 20 and 1:100 000 of women will present with gonadal failure and primary amenorrhoea. In terms of the mode of presentation, premature ovarian failure (POF) is the aetiology of 20% of cases with primary amenorrhoea and 10% of those with secondary amenorrhoea.

Premature ovarian failure (POF) refers to the cessation of ovarian function at an earlier than expected age due to ovarian pathology. Primary ovarian failure is used in two contexts—to describe very early onset ovarian failure presenting with primary amenorrhoea and also to differentiate ovarian pathology from secondary ovarian failure, which refers to lack of ovarian activity as a result of gonadotropin deficiency. Primary ovarian insufficiency is recently favoured as an all-encompassing term that accounts for the variable course and occasional remission (4). The term hypergonadotropic hypogonadism is also used to emphasize ovarian origin. Resistant ovary syndrome (ROS) is an obsolete term, used to describe the coexistence of hypergonadotropic hypogonadism with normal ovarian follicles on histology of the ovary. It was soon realized that women with ROS progressed to complete ovarian failure and that ovarian follicles on histology were commonly found in established ovarian failure, negating the usefulness of this diagnostic label. Very early onset ovarian failure with a known genetic cause is often labelled inaccurately as ‘gonadal dysgenesis’ as in most situations it is thought that early ovarian development is normal.
Polycystic ovary syndrome: reproductive aspects
Authors: Catteau-Jonard Sophie , Gallo Cécile , Didier Didier
Published: July 2011

The polycystic ovary syndrome (PCOS) is the most common cause of anovulation and hyperandrogenism in women, affecting between 5 and 10% of women of reproductive age worldwide (1). Although this difficult topic in endocrine gynaecology is under extensive research, controversies still remain about the pathophysiology, diagnosis, and therapy of PCOS.

The PCOS phenotype can be structured in three components: manifestations of anovulation, hyperandrogenism, and the metabolic syndrome (of which hyperinsulinaemia secondary to insulin resistance is the central abnormality). The latter two are addressed in other chapters. Our knowledge about the mechanism of disturbed folliculogenesis in PCOS that is responsible for its reproductive aspects has much increased these last years, thus opening new avenues for the diagnostic and therapeutic approaches.
Polycystic ovary syndrome: metabolic aspects
Authors: Legro Richard S.
Published: July 2011

Polycystic ovary syndrome (PCOS) is thought to be primarily a disorder that affects women during their reproductive years. The diagnostic criteria reflect ovarian dysfunction, i.e. hyperandrogenism, anovulation, and polycystic ovaries. However, women with PCOS appear to be uniquely insulin resistant, are frequently obese, and may be at risk for a variety of long-term health disorders including diabetes, cardiovascular disease, and cancers. Although the endocrine and reproductive features of the disorder improve with age, the associated metabolic abnormalities, particularly components of the metabolic syndrome, may actually worsen. This chapter will explore the pathophysiology of aberrant insulin action in women with PCOS, recognition of long-term risks, and preventive strategies.
Infertility and assisted reproduction
Authors: Balen Adam
Published: July 2011

Infertility is common. It has recently been suggested that approximately 9% of couples are involuntarily childless, although the exact number inevitably depends on how the complaint is defined (1). Medical definitions of infertility tend to emphasize the immediate problem brought to the consultation, reflecting the typically short-term interaction of many doctors, particularly specialists, with their patients. Most accepted definitions therefore involve the number of months prior to the consultation during which the couple has been exposed to the chance of a pregnancy. When the lifetime experience of a couple’s attempt to raise a family is considered, a quite different picture emerges: studies from Oxford and Copenhagen revealed that at least a quarter of all couples experience unexpected delays in achieving their desired family size (2, 3), although only a half may seek treatment (3).
The endometrium: receptivity, implantation, and endometrial cancer as endocrine disease
Authors: Seppälä Markku , Giudice Linda C.
Published: July 2011

In biological terms, human life is a continuum in which male and female gametes fuse in fertilization (conception) to form an embryo. Usually fertilization takes place in the distal part of fallopian tube where the embryo remains 2–3 days, dividing at 12–15 h intervals. On day 3 the embryo has 8 cells, on day 4 a morula stage has been reached, and on day 5 the embryo forms a blastocyst and enters the uterus. The embryo hatches before it implants in the endometrium, most implantations (86%) occurring between day LH +8 and day LH +11 (1). The most reliable clinical sign of implantation is secretion of human chorionic gonadotropin (hCG) from the embryonic trophoblast into maternal serum and urine.
Parturition
Authors: Werner Erika F. , Norwitz Errol R.
Published: July 2011

Labour is the physiological process by which the products of conception are passed from the uterus to the outside world. Timely onset is the key determinant of perinatal outcome. Although all viviparous animals share this process, the molecular and cellular mechanisms appear to differ in humans. Most animal models have demonstrated that the fetus is in control of the timing of labour. However, the parturition cascade in humans appears to be autocrine/paracrine in nature, thus precluding direct investigation. This chapter summarizes the current knowledge on the biological mechanisms responsible for the onset of labour at term in the human, as well as reviewing the limited treatment options when these mechanisms falter.
Gestational trophoblastic neoplasia
Authors: Savage Philip , Seckl Michael J.
Published: July 2011

Arising from the cells of conception, gestational trophoblastic disease (GTD) forms a spectrum of disorders from the premalignant complete and partial hydatidiform moles through to the malignant invasive mole, choriocarcinoma and very rare placental site trophoblastic tumours (PSTT). The latter three conditions are also collectively known as gestational trophoblastic neoplasia (GTN) and, although uncommon, are important to recognize as this enables life-saving therapy to be commenced. About 10% of molar pregnancies fail to die out after uterine evacuation and transform into malignant GTN that require additional chemotherapy (1). These cases are usually recognized early and therefore rarely prove difficult to treat, with cure rates approaching 100% reported in most modern series (2). However, GTN can also develop after any type of pregnancy including miscarriages, term deliveries, and medical abortions. Such patients are often not suspected of having GTN and may present late with widespread disease associated with a wide variety of medical, surgical, and gynaecological problems (3). The prompt diagnosis and early effective treatment of these women is aided by an awareness and understanding of these rare, but highly curable malignancies and good team-working between physicians, gynaecologists, pathologists, and oncologists
A brief history of endocrinology
Authors: Arnott Robert
Published: July 2011

This chapter traces the history of endocrinology, principally through the nineteenth and the beginning of the twentieth centuries, but also looks further back to antiquity and the early modern period when the function of the glandular system was beginning to be recognized and partly understood. It also takes us through to later in the twentieth century, when therapeutics were developed that could tackle endocrine disease, and at the significant discoveries and those scientists and clinicians who made them, placing them in context of what appears later in this volume.
Endocrinology and evolution: lessons from comparative endocrinology
Authors: Danks Janine A. , Richardson Samantha J.
Published: July 2011

Comparative endocrinology is the study of the endocrine glands and their hormones in different species of animals. It is undergoing a renaissance because of the new tools and techniques provided by genome sequencing and molecular biology. Until relatively recently, characterization and detection of hormones in lower vertebrates relied on biological assays and protein chemistry approaches, whereas now gene sequences can be readily revealed from whole genome sequencing. Gene expression and synthesis can be used to develop antibodies and other reagents for sensitive assays and revealing physiological experiments can be carried out.

Endocrinology traditionally used a range of animal species, including many lower vertebrates. Comparative endocrinology became a separate specialty only in the last 50 years when endocrinologists concentrated on rodents as their model animals. In 1933, Riddle demonstrated that an avian pituitary factor that promoted growth of the pigeon crop-sac was identical to a mammalian pituitary factor that earlier had been found to initiate and maintain milk secretion in mammals. Riddle called this avian factor prolactin and the response of the crop-sac provided a sensitive assay for the detection of human prolactin in pituitary extracts. Pigeon prolactin was the first pituitary hormone to be crystallized and purified in 1937 and led to the purification of mammalian prolactin. Prolactin has a number of roles in lower vertebrates, including a vital role as a hypercalcaemic factor in fish.

The first part of this chapter focuses on the calcium-regulating factors including parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), and stanniocalcin (STC), and the second part will discuss comparative endocrinology of thyroid hormones and transthyretin (a thyroid hormone distributor in blood the cerebrospinal fluid).
Hormones and receptors: fundamental considerations
Authors: Funder John W.
Published: July 2011

The original endocrine physiologists viewed hormones as responses to homoeostatic challenge, any signal a call to arms; the word is thus derived from the classical Greek ωρμαειν‎—‘to arouse’. In the twenty-first century a hormone is a molecule—small or large, protein or lipid—secreted in a regulated fashion from one organ and acting on another. The definition is firmly based on the anatomy of the seventeenth century, the histology of the nineteenth, and the physiology of the twentieth. It has been shaped by convention and clinical specialization: gut hormones are the marches between endocrinology and gastroenterology, and the adrenal medulla the territory of the cardiovascular physician. It has been refined by concepts of paracrine—where the secretion of one cell type in a tissue acts on another cell type in the same tissue—and autocrine, where a particular cell type both secretes and responds to a particular signal. Inherent in the concepts of paracrine and autocrine are that the signal is not secreted into blood or lymph, to be distributed more or less throughout the body, but is made locally to act locally. A very good example of a signalling system with both paracrine and autocrine activities is the neuronal synapse.

Inherent in the concept of the signal is that of a receptor: a signal without a receptor is the sound of one hand clapping. Inherent in the concept of a receptor are two functions: that of being able to discriminate between different signals, and to propagate the signal by activating cell membrane or intracellular signal transduction pathways. Discrimination by a receptor between different circulating potential signals is, in the first instance, a function of the likelihood of a particular signal being able to interact with the receptor, for a period of time sufficient to alter the confirmation of the receptor and thus to trigger propagation. This interaction is commonly referred to as binding, and thus the circulating hormone as a ligand (that which is bound). If the structures of ligand and receptors are such that the initial interaction is followed by formation of strong intermolecular bonds between the two, lessening the possibility of dissociation and the receptor returning to an unliganded state, the receptor is said to have high affinity for the ligand (and vice versa). If the binding is followed by propagation of the ‘appropriate’ signal the ligand is classified as an agonist, or active hormone; if a molecule occupies the binding site on the receptor but does not so alter its structure as to propagate a signal, it is classified as a hormone antagonist (and often, by extension, a receptor antagonist). In the past couple of decades, the concepts of ‘agonist’ and ‘antagonist’ have needed to be refined, as noted subsequently in this chapter.
Measurement of hormones
Authors: Wallace Mike
Published: July 2011

The role of accurate and reliable laboratory testing is particularly important for patients with potential endocrine disorders. The revolution which has taken place in the past 50 years in the methodology of hormone measurement is thus of considerable significance to this patient group. It is difficult to imagine that not too long ago common hormone measurements, such as thyroid function tests, took more than a week to produce. Now we live in a world where same day turnaround is the norm for the high throughput commonly requested tests. This is largely due to advances in the way hormones are measured and results delivered to the practising clinical endocrinologist.

Measuring hormones has always been a challenge as most circulate at extremely low concentrations, typically in the pico- (10–12) or nanomolar (10–9) range, and often in a milieu of closely related and potentially interfering compounds making great demands on method sensitivity and specificity. The most common procedures currently used are immuno- and immunometric assays but gas chromatography mass spectrometry (GCMS) and high-performance liquid chromatography (HPLC) also have a place. Liquid chromatography mass spectrometry (LC-MS/MS) is rapidly gaining acceptance for a limited number of hormone measurements.

It is not the aim of this chapter to provide precise detail on hormone measurement methodology but rather to overview general principles and applications of methods in current use. Attention is drawn to preanalytical and analytical problems which could have significant clinical consequences if not recognized.
Ectopic hormone syndromes
Authors: Ray David W.
Published: July 2011

Production of hormones usually occurs in specialized endocrine glands. Such hormone production is typically under control from higher centres, ultimately the brain, and also subject to complex negative feedback. This results in tight regulation of circulating hormone levels, and affords a mechanism for influencing diverse tissue function throughout the body. Inappropriate hormone production by nonendocrine tissue causes a spectrum of rare syndromes which are important as they are not only a management challenge, but also because they shed light on the regulation of tissue-specific gene expression with widespread ramifications for understanding human physiology. In addition, inappropriate expression of a peptide may be useful as a tumour marker, as for example human chorionic gonadotropin (hCG) or α‎-fetoprotein. This chapter will address the basic mechanisms of ectopic hormone production and will further discuss specific clinical syndromes.
Long-term endocrine sequelae of cancer therapy
Authors: Murray Robert D.
Published: July 2011

Over the past 40 years cure rates for childhood malignancies have improved at a remarkable pace. Overall 5-year survival improved from less than 30% in 1960 to more than 70% in 1990. With increasing cure rates, came recognition of the long-term detrimental effects of radiotherapy and chemotherapy on multiple organ systems. Five-year survival has, however, altered little over the last decade. To improve upon recent successes will probably necessitate the use of more complex treatment regimens, resulting in a higher prevalence of adverse treatment-associated long-term effects in these individuals.

Over the next decade the long-term sequelae of childhood cancer therapy is likely to have a significant financial and workforce demand on health services. It is estimated that one in 640 adults aged 20–39 years in the USA is currently a survivor of childhood cancer, and in the UK by 2010 one in 715 young adults is estimated to be a survivor of childhood cancer. Epidemiological data from the American Childhood Cancer Survivors Study (CCSS) reported survivors of more than 5 years to have a 10.8 fold excess in overall mortality (1). The majority of deaths (67%) relate to recurrence of the original tumour. After exclusion of deaths relating to recurrence or progression of the original tumour, mortality rates remained significantly increased. Standardized mortality rates for second malignancies (SMR 19.4), cardiac disease (SMR 8.2), pulmonary disease (SMR 9.2), and other causes (SMR 3.3) were significantly elevated. Long-term endocrine sequelae are particularly prevalent in childhood cancer survivors with 43% of the CCSS cohort reporting one or more endocrinopathies (2). Endocrine late effects include disturbances of growth and puberty, hypothalamopituitary dysfunction, hypogonadism, subfertility, thyroid dysfunction, benign and malignant thyroid nodules, hyperparathyroidism, and reduced bone mass (Table 11.1.3.1–11.1.3.3).
Endocrine treatment of breast cancer
Authors: Sheri Amna , Johnston Stephen
Published: July 2011

Endocrine manipulation has been recognized as a treatment modality for breast cancer for over 100 years. Oestrogen is an important promoter in the pathogenesis of breast cancer and endocrine response, for the most part, is dependent on the presence of oestrogen receptor, a protein which can be detected in about 70% of primary breast cancers.

Historically, treatments 30–40 years ago involved surgical removal of endocrine glands such as the ovaries, adrenal glands, or hypophysis. However, a better understanding of the mechanisms that result in oestrogenic deprivation of breast cancer cells has enabled medical therapeutics to be developed which have largely replaced surgical ablative procedures (Box 11.2.1.1). Firstly, hormonal manipulation can be achieved at a cellular level by competing for oestrogen receptor in the breast tumour, using so-called antioestrogens, such as tamoxifen which, although antioestrogenic on breast cancer cells, can have oestrogenic effects in other tissues. More antioestrogenic agents known as selective oestrogen receptor modulators (SERMs), and ‘pure’ antioestrogens such as fulvestrant have now been developed that have little or no oestrogenic effects, and these are being clinically evaluated.

An alternative approach is to lower systemic oestrogen levels in premenopausal women by the use of luteinizing hormone releasing hormone (LHRH) agonists and in postmenopausal women by the use of aromatase inhibitors, which block oestrogen synthesis in nonovarian tissues. Additional, endocrine agents with more ill-defined mechanisms, such as progestogens, androgens, and corticosteroids, can also cause endocrine responses.

In patients with oestrogen receptor-positive advanced breast cancer, endocrine treatments in general achieve a response rate of between 20 and 40%, according to the type of therapy and prior exposure to endocrine treatment. Predictors of response to hormone therapy include a previous response to endocrine treatment, the site of metastases, coexpression of progesterone receptor, and the age of the patient. The median response duration to endocrine therapy in advanced disease is about 8–14 months and for some patients response duration can last several years.

In patients with early stage oestrogen receptor-positive breast cancer, adjuvant endocrine therapy given for 5 years after primary surgery delays local and distal relapse and prolongs survival. It also substantially reduces the incidence of contralateral breast cancer in patients with primary breast cancers, and similarly will reduce the incidence of breast cancer in healthy women by about 50%. As such, endocrine therapy can be used as chemoprevention of breast cancer.

Overall, the development of relatively low toxicity endocrine treatments for advanced and for operable breast cancer has had a substantial impact on the management of this disease, and the types of treatment will be reviewed in this chapter.
Hormonal therapy of prostate cancer
Authors: O’Hanlon Brown Ciara , Waxman Jonathan
Published: July 2011

Prostate cancer is the most common cancer to effect men and the second most common cause of cancer-related death. Premalignant change or prostatic intraepithelial neoplasia has been detected within the prostate glands of men under 30 years of age. The incidence of prostate cancer remains negligible until men reach their 40s from whence it rises steadily and by 80 years 70% of men have detectable tumours at autopsy (1).

A majority of prostate cancers arise from the peripheral zone of the prostate and rarely cause obstructive symptoms. Consequently, prostate cancers have historically presented late, with symptoms of metastatic disease. The advent of prostate-specific antigen (PSA) testing has produced a stage shift so that at present over 90% of prostate cancers are diagnosed as organ-confined disease. PSA diagnosis has unmasked a subset of prostate tumours that exhibit an indolent growth pattern and appear destined to remain organ-confined tumours the patient dies with, and not from. US SEER data estimates a 50-year-old man has a 42% chance of developing prostate cancer but only a 3.6% chance of dying from the disease. Features, either clinical or molecular, which would allow clinicians to clearly differentiate indolent from aggressive disease while still at the organ-confined stage, have yet to be identified (1).

Adenocarcinoma is the predominant histological subtype of prostate cancer, accounting for 95% of tumours. Prostatic adenocarcinomas arise from androgen receptor-positive epithelial cells. On histological examination, prostate cancers appear multifocal and demonstrate heterogeneity both within individual tumours and across populations. This has created an obstacle as researchers attempt to subclassify prostate cancer and identify the molecular defects responsible for driving prostatic carcinogenesis (1). Of prostate cancers, 80–90% are androgen receptor-positive at diagnosis (2), thus to date the androgen–androgen receptor axis is the sole molecular feature of this disease that has been successfully harnessed as a therapeutic target.