Various epidemiological studies have shown an aetiological link between vitamin D deficiency and cancer incidence. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], has potent anti-cancer activities both in vitro and in vivo. These anti-cancer effects are attained by regulating the transcription of numerous genes that are involved in different pathways to reduce tumorigenesis and are dependent on the cancer cell type. Besides reducing cell growth and inducing apoptosis, 1,25(OH)₂D₃ also inhibits angiogenesis and metastasis. Moreover, its potency to inhibit inflammation also contributes to its anti-tumoral activity. Here, we report the different ways in which 1,25(OH)₂D₃ interferes with the malignant processes that are activated in cancer cells.
Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.
Normally, one inherits one chromosome of each pair from one parent and the second chromosome from the other parent. Uniparental disomy (UPD) describes the inheritance of both homologues of a chromosome pair from the same parent. The biological basis of UPD syndromes is disturbed genomic imprinting. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin. Phenotypes range from unapparent to unmasking of an autosomal-recessive disease to presentation as a syndromic imprinting disorder. Whilst paternal UPD(7) is clinically unapparent, maternal UPD(7) is one of several causes of Silver-Russell syndrome. Presentation of paternal UPD(14) ("Kagami syndrome") is a thoracic dysplasia syndrome with mental retardation and limited survival. Findings in maternal UPD(14) ("Temple") syndrome show an age-dependent overlap with the well-known maternal UPD(15) (Prader-Willi) syndrome and are dominated by initial failure to thrive followed by obesity, learning difficulties and precocious puberty. Diagnostic strategies to tackle the genetic heterogeneity of UPD(7) and UPD(14) syndromes will be explained. Management issues in UPD(7) and UPD(14) patients will be discussed, and finally areas requiring further research will be outlined.
A continuum of increasing risk of adulthood diseases, such as cardiovascular disease, type 2 diabetes and hypertension, with decreasing size at birth is now well-reported and a number of different hypotheses have been proposed. Birthweight links with disease risk markers such as insulin resistance are apparent from childhood, particularly when low birthweight is followed by rapid postnatal weight gain and childhood obesity. Such growth patterns follow fetal growth restraint, associated with maternal-uterine factors such as primiparity, smoking, maternal genes or variations in maternal diet. The fetal metabolic and hormonal responses to intrauterine growth restraint and to rapid postnatal growth are likely to be key to the early pathogenesis of adulthood disease. Thrifty fetal genotypes may enhance these adaptations and improve perinatal survival but predispose to adulthood disease. Their historical selection could explain high prevalences of type 2 diabetes in some ethnic groups, and their identification could allow targeting of potential interventions.
Bone modelling prevents the occurrence of damage by adapting bone structure - and hence bone strength - to its loading circumstances. Bone remodelling removes damage, when it inevitably occurs, in order to maintain bone strength. This cellular machinery is successful during growth, but fails during advancing age because of the development of a negative balance between the volumes of bone resorbed and formed during remodelling by the basic multicellular unit (BMU), high rates of remodelling during midlife in women and late in life in both sexes, and a decline in periosteal bone formation. together resulting in bone loss and structural decay each time a remodelling event occurs. The two steps in remodelling - resorption of a volume of bone by osteoclasts and formation of a comparable volume by osteoblasts - are sequential, but the regulatory events leading to these two fully differentiated functions are not. Reparative remodelling is initiated by damage producing osteocyte apoptosis, which signals the location of damage via the osteocyte canalicular system to endosteal lining cells which forms the canopy of a bone-remodelling compartment (BRC). Within the BRC, local recruitment of osteoblast precursors from the lining cells, the marrow and circulation, direct contact with osteoclast precursors, osteoclastogenesis and molecular cross-talk between precursors, mature cells, cells of the immune system, and products of the resorbed matrix, titrate the birth, work and lifespan of the cells of this multicellular remodelling machinery to either remove or form a net volume of bone appropriate to the mechanical requirements.
Size at birth has been associated repeatedly with increased risk of cardiovascular morbidity and mortality later in life. However, there is accumulating evidence to suggest an association between being born small for gestational age (SGA) and increased risk of lower intelligence, poor academic performance, low social competence and behavioural problems, compared with individuals born appropriate for gestational age. Crude neurological handicaps, such as cerebral palsy, are extremely rare in children born SGA at term. Such handicaps are more common in very premature children. However, there does appear to be an increase in the risk for non-severe neurological dysfunction in individuals born SGA. Intellectual performance is evaluated in young children in several different ways, including standardized tests such as Weschler's Intelligence Scale - Revised, and teachers and parents' reports. In adulthood, indirect variables such as education and occupation are used in addition to standardized tests. It may be possible to modify the effects of SGA on intellectual development by breast feeding the baby for more than 6 months. Nutrient-enriched formula does not have any advantages when it comes to intellectual development, and induces a risk of rapid weight gain and eventually overweight. Growth hormone treatment may also have some effect on intelligence quotient.
Laboratory studies have found that short-term sleep restriction is associated with impairments in glucose metabolism, appetite regulation and blood pressure regulation. This chapter reviews the epidemiologic evidence for an association between habitual sleep duration and quality and risk of cardiometabolic diseases including obesity, diabetes and hypertension. Multiple studies observed a cross-sectional association between short sleep duration (generally <6 h per night) and increased body mass index or obesity, prevalent diabetes and prevalent hypertension. Many studies also reported an association between self-reported long sleep duration (generally >8 h per night) and cardiometabolic disease. There have been a few prospective studies and several, but not all, have found an association between short sleep and incident diabetes, hypertension and markers of cardiovascular disease. Future prospective epidemiologic studies need to include objective measures of sleep, and intervention studies are needed in order to establish a causal link between impaired or insufficient sleep and cardiometabolic disease risk.
The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that respectively bind a bowl-like ligand configuration (gene transcription) or a planar-like ligand shape (rapid responses). When occupied by 1α,25(OH)₂D₃, the VDR-GP interacts with the retinoid X receptor to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1α,25(OH)₂D₃. By recruiting complexes of either coactivators or corepressors, activated VDR modulates the transcription of genes encoding proteins that promulgate the traditional genomic functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. 1α,25(OH)₂D₃/VDR control of gene expression and rapid responses also delays chronic diseases of aging such as osteoporosis, cancer, type-1 and -2 diabetes, arteriosclerosis, vascular disease, and infection.
The Institutes of Medicine (IOM) recently revised the recommended dietary allowances (RDA) for vitamin D, to maintain serum 25-hydroxyvitamin D (25(OH)D) at or above 50 nmol/L, to sustain bone density, calcium absorption, and to minimize risk of osteomalacia and rickets. However there are compelling reasons why 25(OH)D should preferably exceed 75 nmol/L: (A) Scrutiny of actual data specified by the IOM relating 25(OH)D to bone density and osteomalacia shows the desirable minimum 25(OH)D to be 75 nmol/L (30 ng/mL). (B) Humans are primates, optimized through evolution to inhabit tropical latitudes, with serum 25(OH)D over 100 nmol/L. (C) Epidemiologic relationships show health benefits if 25(OH)D levels exceed 70 nmol/L; these include fewer falls, better tooth attachment, less colorectal cancer, improved depression and wellbeing. Some studies of populations at high-latitude relate higher 25(OH)D to risk of prostate cancer, pancreatic cancer or mortality. Those relationships are attributable to the dynamic fluctuations in 25(OH)D specific to high latitudes, and which can be corrected by maintaining 25(OH)D at steady, high levels throughout the year, the way they are in the tropics. (D) There are now many clinical trials that show benefits and/or no adversity with doses of vitamin D that raise serum 25(OH)D to levels beyond 75 nmol/L. Together, the evidence makes it very unlikely that further research will change the conclusion that risk of disease with serum 25(OH)D higher than 75 nmol/L is lower than the risk of disease if the serum 25(OH)D is approximately 53 nmol/L.
3M syndrome (MIM 273750) is an autosomal recessive disorder characterized by pre- and post-natal growth retardation (<-4 SD), facial dysmorphism, large head circumference, normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies. There is no specific treatment. Up till now, mutations in either CUL7 or OBSL1 genes have been identified in this rare disorder. There are no clinical or radiological differences between patients with CUL7 or OBSL1 mutations. CUL7 appears to be the major gene responsible for 3M syndrome accounting for 77.5% of cases while OBSL1 mutations accounts for 16.3%. A few patients have no mutations in these genes suggesting the involvement of a third gene.
Endocrine-disrupting chemicals (EDCs) are typically identified as compounds that can interact with oestrogen or androgen receptors and thus act as agonists or antagonists of endogenous hormones. Growing evidence shows that they may also modulate the activity/expression of steroidogenic enzymes. These are expressed not only in the adrenal glands and gonads but also in many tissues that have the ability to convert circulating precursors into active hormones. In this way, EDCs may impact both on sexual differentiation and development and on hormone-dependent cancers. This review summarizes the evidence for EDCs as modulators of steroidogenic enzymes, identifies the structure/activity relationship in terms of inhibiting specific enzyme activity, questions whether experimental observations can equate with natural in vivo exposure or dietary intake of EDCs, and finally looks at the mechanisms through which these chemicals may disrupt normal steroidogenesis. In summarizing the evidence, the question of whether or not the dietary intake of these endocrine disrupters could pose a threat to human sexual development and health will be addressed.
Insensitivity to the action of androgens is a common cause of undermasculinisation in 46,XY individuals. These disorders are a result of the failure of major androgens to act via the intracellular androgen receptor and, thus, the genomic effects of androgen signalling are disrupted. The phenotype of affected individuals can vary considerably, depending on the dysfunction of the receptor. In childhood, the diagnosis is often complicated due to the lack of sensitive biochemical determinants, whilst during adolescence and in adults, the diagnosis can be readily made because of the striking clinical feminisation and a conclusive laboratory analysis. A variety of mutations in the androgen receptor have been analysed, providing insight into the complex pathways of intracellular processing and signal transduction via the androgen receptor. Endocrine therapy in androgen-insensitivity syndrome is controversial, because till date the special hormonal profiles in androgen insensitivity have not been acknowledged in replacement strategies.
The 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male, it is the foetal adrenal that produces the DHT precursors in the female. By understanding the principles of human steroid biosynthesis, the pathogenesis of each disorder may be logically deduced, and treatment strategies are rationally constructed. In practice, however, therapies for many of these diseases are fraught with complications and caveats, and current approaches leave much room for improvement. This review discusses these diseases, their pathogenesis and approaches to therapy. We emphasise areas where improved treatments are sorely needed.
Disorders of androgen production can occur in all steps of testosterone biosynthesis and secretion carried out by the foetal Leydig cells as well as in the conversion of testosterone into dihydrotestosterone (DHT). The differentiation of Leydig cells from mesenchymal cells is the first walk for testosterone production. In 46,XY disorders of sex development (DSDs) due to Leydig cell hypoplasia, there is a failure in intrauterine and postnatal virilisation due to the paucity of interstitial Leydig cells to secrete testosterone. Enzymatic defects which impair the normal synthesis of testosterone from cholesterol and the conversion of testosterone to its active metabolite DHT are other causes of DSD due to impaired androgen production. Mutations in the genes that codify the enzymes acting in the steps from cholesterol to DHT have been identified in affected patients. Patients with 46,XY DSD secondary to defects in androgen production show a variable phenotype, strongly depending of the specific mutated gene. Often, these conditions are detected at birth due to the ambiguity of external genitalia but, in several patients, the extremely undervirilised genitalia postpone the diagnosis until late childhood or even adulthood. These patients should receive long-term care provided by multidisciplinary teams with experience in this clinical management.
Androgens play an essential role in prostatic development and function, but are also involved in prostate disease pathogenesis. The primary prostatic androgen, dihydrotestosterone (DHT), is synthesized from testosterone by 5alpha-reductase types 1 and 2. Inhibition of the 5alpha-reductase isoenzymes therefore has potential therapeutic benefit in prostate disease. The two currently approved 5alpha-reductase inhibitors (5ARIs), finasteride and dutasteride, have demonstrated long-term efficacy and safety in the treatment of benign prostatic hyperplasia. Finasteride, a type-2 5ARI, has also been studied for its ability to reduce the incidence of biopsy-detectable prostate cancer in the Prostate Cancer Prevention Trial. Treatment with dutasteride, a dual 5ARI, has been shown to result in a greater degree and consistency of DHT suppression compared with finasteride. Two large-scale studies of dutasteride are currently investigating the role of near-maximal DHT suppression in the settings of prostate cancer risk reduction and expectant management of localized prostate cancer.
Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions occurring in around 1 per 300,000 live births. In TNDM, growth-retarded infants develop diabetes in the first few weeks of life, only to go into remission after a few months with possible relapse to permanent diabetes usually around adolescence or in adulthood. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. The very recently elucidated mutations in KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunits of the pancreatic K(ATP) channel involved in regulation of insulin secretion, account for a third to a half of the PNDM cases. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provides a tool for distinguishing transient from permanent neonatal diabetes mellitus in the neonatal period. Some patients (those with mutations in KCNJ11 and ABCC8) may be transferred from insulin therapy to sulphonylureas.
Food, dietary fibre and espresso coffee interfere with the absorption of levothyroxine. Malabsorptive disorders reported to affect the absorption of levothyroxine include coeliac disease, inflammatory bowel disease, lactose intolerance as well as Helicobacter pylori (H. pylori) infection and atrophic gastritis. Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine.
This chapter describes evolving patterns of drug misuse in sport, and reciprocal systems for defining and detecting doping, across the late twentieth century. The International Olympic Committee's list of prohibited substances and methods is presented as a primary tool for developing and administering such systems. Developments in the list since its introduction have been stimulated both by increasingly sophisticated detection methods, and by the imperative to recognise and anticipate trends in doping. The historical argument that doping is incompatible with the ethical nature of sport, and relates to pressures and inducements to misuse drugs, particularly at the élite level, is also addressed. Finally, recent developments in international collaboration between governments and the sporting community are covered, and continued efforts to harmonize standards in anti-doping policies and practices are advocated.
Doping with growth hormone (GH) has become an increasing problem in sports during the last 10 years. GH has a reputation of being fairly effective among GH users, although the effectiveness is not undisputed, and the few controlled studies that have been performed with supraphysiological GH doses to athletes have shown no significant positive effects of GH in the aspect of a doping agent. There is no method yet to discover GH doping, but current intensive research in this matter will hopefully produce a method in the years to come. This article describes the GH physiology, the clinical use of GH, the athlete's view, administration regimens and side effects.
Atherosclerotic cardiovascular disease (CVD) is the main cause of death in developed and developing countries. It is well accepted that several diseases - including hypertension, dyslipidemia and diabetes mellitus - increase CVD. More recently also chronic inflammatory diseases, such as rheumatoid arthritis, have been shown to accelerate CVD. This association further supports a responsible role for inflammatory processes in all stages of CVD pathophysiology. Clinically, CVD ranges through different acute and chronic syndromes with ischemic symptoms in distal tissues, including heart, cerebral region or peripheral arteries. Several treatments for reducing CVD are under investigation. In this review we focus on statins, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin-II receptor blockers (ARBs), updating therapeutic evidence from the last clinical trials with particular relevance to diabetic patients.
Free fatty acids (FFAs) circulate round the body and represent important nutrients and the key oxidative fuel for the heart and resting skeletal muscle. In addition, FFAs are thought to be potent signalling molecules. Growing evidence indicates that FFAs may be involved in type 2 diabetes mellitus and obesity by mediating insulin resistance. In 1963, it was postulated that accumulated glucose-6-phosphate as a result of increased FFA oxidation leads to decreased glucose uptake. An alternative hypothesis is that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity, which appears to be a consequence of decreased insulin receptor substrate-1-associated phosphatidyl inositol 3 kinase activity. Moreover, FFAs can arise locally, and increased intramyocellular and hepatocellular lipids have been shown to be associated with insulin resistance. This paper reviews the main aspects of FFA metabolism in the development of insulin resistance in skeletal muscle and liver, as well as the role of ectopic lipid deposits as a local source of FFAs. Finally, the role of thiazolidinediones as modulators of FFA-induced insulin resistance will be discussed.
Hirsutism and acne are common and highly distressing complaints in women with polycystic ovary syndrome (PCOS). Drugs are only partially effective on terminalized hairs, and removal of these hairs is usually required. Therefore, management of hirsutism is generally based upon a dual approach: a pharmacological therapy to reduce androgen secretion and/or androgen action, and removal of terminal hair already present. Ovarian suppression of androgen secretion with oral contraceptives is widely used in these women, but its efficacy appears limited. The most effective medical therapy for hirsutism is by anti-androgen drugs. Electrolysis and laser photothermolysis are considered the most effective cosmetic procedures, although the effects of these methods should not be considered permanent. Acne may be treated with different tools, according to the severity of the condition and other characteristics of the patient. These tools include topical and systemic retinoids and antibiotics, topical antibacterial agents, androgen suppression by oral contraceptives, and anti-androgen drugs.
Acromegaly is a rare, chronic condition caused by sustained and unregulated oversecretion of growth hormone (GH), usually attributed to a pituitary adenoma. Prolonged exposure to excessive amounts of GH and its target hormone, insulin-like growth factor-1 (IGF-1), results in pronounced metabolic changes and tissue enlargement that ultimately lead to increased morbidity and early mortality. As early diagnosis of acromegaly can have substantial beneficial effects on quality of life and overall survival for patients, it is important that the tests used to diagnose the condition are accurate, with highly reproducible results. The first kits used to measure GH and IGF-1 were radioimmunoassay, with many limitations that necessitated the development of more sensitive tools. Newer assays, although better than previous assays, are far from ideal. Simple changes that may improve the testing process include the adoption of mass units for GH interpretation and the use of a single recombinant calibrant. Furthermore, the conversion factors and reference ranges used to describe the normal limits for GH and IGF-1 levels require refinement. Physicians should be aware of the GH and IGF-1 assays used in their reference laboratories, and ensure that they know the appropriate assay cut-off values, to avoid misinterpreting results.
Because growth hormone and IGF-1 both have regulatory roles in the cardiovascular system, patients with acromegaly often present with abnormalities of heart structure and function and the vascular system, which if left unmanaged can reduce life expectancy. Early symptoms of acromegalic cardiomyopathy (hyperkinetic syndrome) can be characterized by cardiac hypertrophy, increased heart rate, and increased systolic output. When left untreated, more pronounced hypertrophy, signs of diastolic dysfunction and insufficient systolic function on exertion arise, and can lead to systolic dysfunction at rest, and eventually heart failure with signs of dilative cardiomyopathy. Increasingly, evidence suggests that early diagnosis and treatment of acromegaly (before the age of 40 years) can help prevent the progression of cardiovascular disease, improve quality of life, and reduce the risk of premature mortality. This review focuses on management strategies for newly diagnosed patients with acromegaly and evidence of cardiovascular disease. The roles of surgery and medical treatment are discussed in the context of using optimal treatment strategies to help reverse cardiac hypertrophy and normalize other cardiac risk factors.
Excessive production of the growth hormone (GH) is responsible for acromegaly. It is related to a pituitary GH-secreting adenoma in most cases. Prevalence is estimated 40-130 per million inhabitants. It is characterised by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory and metabolic consequences determine its prognosis. The diagnosis is confirmed by an increased serum GH concentration, unsuppressible by an oral glucose load and by detection of increased levels of insulin-like growth factor-I (IGF-I). Treatment is aimed at correcting (or preventing) tumour compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. When surgery, the usual first-line treatment, fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used. The GH-receptor antagonist (pegvisomant) is helpful in patients who are resistant to somatostatin analogues. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most cases, allowing a normal life expectancy.
Acromegaly is an endocrine disorder characterized by sustained hypersecretion of growth hormone (GH) with concomitant elevation of insulin-like growth factor I (IGF-I) associated with premature mortality from cardiopulmonary diseases and certain malignancies. In particular, there is a two-fold increased risk of developing colorectal cancer. Possible mechanisms underlying this association include elevated levels of circulating GH and IGF-I, but several other plausible processes may be relevant. In a parallel literature, there has been debate whether GH replacement therapy is associated with increased cancer risk in three scenarios: (1) tumour recurrence in children with previously treated cancer; (2) second neoplasms (SNs) in survivors of childhood cancer treated with GH; and (3) de-novo cancer in non-cancer patients treated with GH. The general evidence suggests no increased risk in scenario 1. Through a maze of complex study designs, there is inconclusive evidence of a very modest increase in cancer risk in treated GH-deficiency patients in scenarios 2 and 3, but it is likely that the cumulative risk equates to that of the general population. This emphasizes the need for patient selection balanced against the known morbidity of untreated GH deficiency.
Knowledge of the interaction between growth hormone (GH) and the growth hormone receptor (GHR) has led to the rational design of a GHR antagonist. An analogue of GH able to block the action of GH at the cellular level offers greater specificity of effect compared with current medical therapies and is not dependent on tumour characteristics. This chapter reviews the interaction between GH and the GHR, and discusses the outstanding issues regarding GHR antagonist therapy in acromegaly.
Thyroid dermopathy that occurs in 4–13 % of patients with Graves’ ophthalmopathy is an extrathyroidal manifestation of Graves’ disease. Thyroid acropachy commonly presents with clubbing of digits and occurs in 20 % of patients with dermopathy. Basic pathogenesis of dermopathy is similar to ophthalmopathy. Presence of TSH receptor in the fibroblasts and its interaction with TSH receptor antibodies and stimulation of fibroblasts resulting in production of glycosaminoglycans is the most likely immune process. Localization of thyroid dermopathy to lower extremity is explained by mechanical factors such as dependency of the lower extremity.
Measures for prevention and treatment of dermopathy include optimal and rapid normalization of thyroid function and early local corticosteroid therapy for existing pretibial myxedema. Systemic therapies used in ophthalmopathy can be tried in refractory cases not responding to local corticosteroid therapy. In future any systemic therapy proven to be beneficial for ophthalmopathy can be used empirically for refractory cases of dermopathy.
For thyroid acropachy no specific therapy has been reported and management should be preventive and local therapy for associated dermopathy of hands and feet. In severe cases of acropachy with painful periosteal reaction, pain management will be needed.
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most common cause of euvolaemic hyponatraemia. However, although first described over 50 years ago, the management of hyponatraemia secondary to SIADH is not always straightforward. Some of the issues surrounding the management of hyponatraemia secondary to SIADH were explored in the European Hyponatraemia Survey completed by attendees of the European Hyponatraemia Network Academy Meeting 2011. This article describes the findings of this survey and the specific issues raised regarding the management of hyponatraemia secondary to SIADH in Europe. Some of these issues - including awareness, education, diagnosis, management and cost considerations of the condition - were common to countries across Europe.
Adrenocorticotropic hormone- (ACTH-)independent macronodular adrenal hyperplasia (AIMAH) is an infrequent cause of Cushing's syndrome (CS). AIMAH presents as incidental radiological finding or with subclinical or overt CS, occasionally with secretion of mineralocorticoids or sex steroids. The pathophysiology of this entity is heterogeneous. The aberrant adrenal expression and function of one or several G-protein-coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis. In several familial cases of AIMAH, specific aberrant hormone receptors are functional in the adrenal of affected members. Additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition in the various nodules over time. Other mechanisms, such as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion, have been rarely identified in other cases of AIMAH. The identification of aberrant receptors can offer a specific pharmacological approach to prevent progression and control abnormal steroidogenesis; alternatively, unilateral or bilateral adrenalectomy becomes the treatment of choice.
Inherited adrenocorticotropin (ACTH) resistance diseases are rare and include triple A syndrome and familial glucocorticoid deficiency (FGD). These conditions show genetic heterogeneity, i.e., the identical clinical phenotype may result from defects in more than one gene. Clinically, FGD is characterized only by ACTH resistance, while the triple A syndrome exhibits a variety of additional clinical features. FGD is caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) and the recently identified melanocortin 2 receptor accessory protein (MRAP) genes. In addition, linkage to a locus on chromosome 8 has been demonstrated. The identification of further genes in ACTH resistance syndromes may reveal novel aspects of MC2R signalling and trafficking. This review will summarize the clinical, biochemical and genetic aspects of these rare but informative diseases.
Thyroid hormones (THs) have important effects on cellular development, growth, and metabolism. They bind to thyroid hormone receptors (TRs), TRalpha and TRbeta, which belong to the nuclear hormone receptor superfamily. These receptors also bind to enhancer elements in the promoters of target genes, and can regulate both positive and negative transcription. Recent emerging evidence has characterized some of the molecular mechanisms by which THs regulate transcription as co-repressors, and co-activators have been identified and their effects on histone acetylation examined. THs also have rapid effects that do not require transcription. These can occur via TRs or other cellular proteins, and typically occur outside the nucleus. It appears that THs regulate multiple cellular functions using a diverse array of receptors and signaling systems. TR isoform- or pathway-specific drugs might provide the therapeutic benefits of TH action such as decreasing obesity or lowering cholesterol levels without some of the side effects of hyperthyroidism.
Sex steroid signalling determines female and male sexual development and maintains the female and male phenotype in adults. Steroids carry out their function by activation of their cognate intracellular receptor, which is a ligand-dependent transcription factor. Steroid receptors function by binding to specific structural elements in the regulatory regions of target genes and by recruitment of cofactors by protein-protein interaction. Cofactors might display enzymatic activities that modify histones and other proteins. Cofactors also include proteins that modulate the chromatin structure and protein complexes that function as bridging factors between the multi-protein complexes. This review focuses mainly on the function of the androgen receptor and its cofactors and their role in androgen insensitivity syndrome.
Dipeptidyl-peptidase IV (DPP-4) inhibitors inhibit the degradation of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The first available DPP-4 inhibitors are sitagliptin and vildagliptin. These compounds are orally active and have been shown to be efficacious and well tolerated. Two additional DPP-4 inhibitors are under review, and there are several others in clinical development. This article gives an overview on the mechanism of action of DPP-4 inhibitors and focuses on their development and their important physiological actions with regard to the treatment of type 2 diabetes.
A number of mutations that disturb the development and function of the hypothalamic-pituitary-gonadal (HPG) axis and cause disturbances in pubertal development are known today. These mutations have effects at all levels of the HPG axis, from the migration of gonadotrophin releasing hormone (GnRH) neurones from the nasal cavity to the hypothalamus, GnRH secretion, GnRH action, pituitary gonadotroph differentiation, gonadotrophin synthesis and secretion, right through to gonadotrophin action. Most of the mutations are inactivating, thus causing hypogonadism and arrest or delay of pubertal development. One exception is the activating mutations of the LH receptor, which causes the male-limited gonadotrophin-independent precocious puberty. The human mutations and animal models with disrupted function of orthologous genes have clarified the molecular pathogenesis of hypogonadism and disturbances of pubertal development. The correct diagnosis of these disorders using molecular biological techniques is now possible. This allows the selection of specific treatments and correct counselling of the patients and their families.
The global epidemic of obesity and type-2 diabetes has heightened the need to understand the mechanisms that contribute to its pathogenesis and also to design and trial novel treatments. Patients with glucocorticoid (GC) excess--'Cushing's syndrome'--are phenotypically similar to patients with simple obesity. As such, much research has focused on the manipulation of local GC action as a therapeutic strategy. The majority of the classical actions of GCs are mediated via activation of the glucocorticoid receptor (GR). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive cortisone to cortisol and therefore amplifies local GC action. There is now a wealth of data from rodent and clinical studies implicating this conversion in the pathogenesis of obesity, type-2 diabetes, and the metabolic syndrome. Selective 11beta-HSD1 inhibitors (selective in that they block the activity of 11beta-HSD1 and not 11beta-HSD2 which inactivates cortisone to cortisol in mineralocorticoid target tissues) are currently in development although not yet available for use in clinical studies. Rodent studies utilizing these compounds have shown dramatic improvements in insulin sensitivity as well as improvements in lipid profiles and atherogenesis. A further experimental approach has been to design drugs that antagonize GR activation, and again these compounds appear to improve insulin sensitivity and lower glucose production rates. The key test for both of these research strategies is whether they will translate into clinical studies, and results from these trials are now eagerly awaited.
The analysis of mice that lack systemically the actions of the active form of vitamin D, 1,25(OH)₂D, has shown that 1,25(OH)₂D is an essential regulator of calcium homeostasis and that its actions are aimed at maintaining serum calcium levels within narrow limits. Especially the stimulation of intestinal calcium transport by 1,25(OH)₂D is important for calcium and bone homeostasis. The involved transporters are however still elusive. The targeted deletion of 1,25(OH)₂D action in chondrocytes has provided compelling evidence for a paracrine control of bone development and endocrine regulation of phosphate homeostasis by 1,25(OH)₂D. Targeting vitamin D receptor (VDR) function in other tissues will further enhance our understanding of the cell-type specific action of 1,25(OH)₂D. In this review, we will discuss the current understanding and remaining questions concerning the calcemic actions of 1,25(OH)₂D in the intestine, kidney and bone, with special focus on the evidence obtained by the use of transgenic mouse models.
The thyrotropin receptor (TSHR) is a G-protein-coupled receptor with a large ectodomain. TSH, acting via TSHR, regulates thyroid growth and thyroid hormone production and secretion. The TSHR undergoes complex post-translational processing involving dimerization, intramolecular cleavage, and shedding of its ectodomain, and each of these processes may influence the antigenicity of the TSHR. The TSHR is also the major autoantigen in Graves' disease, as well as a leading candidate autoantigen in both Graves' ophthalmopathy and pretibial myxedema. The naturally conformed TSHR is most effectively presented as an autoantigen to the immune system, causing the production of stimulating TSHR-Abs. There are also autoantibodies which block the TSHR from TSH action, and neutral TSHR-Abs which have no influence on TSH action. TSHR-Abs can be detected by competition assays of TSHR-Abs for labeled TSH, or monoclonal TSHR-Ab binding to solubilized TSHRs, or by bioassays using thyroid cells or mammalian cells expressing recombinant TSHRs.
This article focusses on the antidiabetic therapeutic potential of the incretin hormone glucagon-like peptide-1 (GLP-1) in the treatment of patients with type 2 diabetes mellitus (T2DM). T2DM is characterised by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion, which in combination eventually result in hyperglycaemia and, in the longer term, microvascular and macrovascular diabetic complications. Traditional treatment modalities - even multidrug approaches - for T2DM are often unsatisfactory in making patients reach glycaemic goals as the disease progresses caused by a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens and safety and tolerability issues, the latter including hypoglycaemia, body weight gain, oedema and gastrointestinal side effects. Therefore, the actions of GLP-1, which include the potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion and suppresses food intake and appetite.
In recent years, the thiazolidinediones (e.g. rosiglitazone, pioglitazone) have emerged as an exciting novel class of therapeutic agent for the treatment of type 2 diabetes mellitus and the human metabolic syndrome. At first glance, the use of these high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, that promote adipogenesis, to treat a group of disorders that typically have their origins in obesity seems counter-intuitive. However, to view PPARgamma simply as a regulator of fat mass, and adipocytes themselves as passive vessels for energy storage, is to ignore an extensive body of data that speaks of the diverse roles of both this receptor and adipose tissue in the maintenance of normal metabolic homeostasis. This article highlights the important clinical and laboratory observations made in human subjects harbouring genetic variations in PPARgamma that have confirmed its pivotal role in the regulation of adipocyte endocrine function, and thus our metabolic response to the environment.
Stress responses play a crucial adaptive role but impose potentially subversive demands on the organism. The same holds for the symptoms of illness as seen after immune activation by pathogens or tissue damage. The responses to immune stimuli and stressors show remarkable similarities and rely on similar control mechanisms in the brain: i.e. they involve neuropeptides of the corticotropin releasing factor (CRF) family. Immune and non-immune challenges lead to responses that normally show a temporal relationship with the duration and intensity of the stimulus and the (re)activity of the stress-responsive systems return to their pre-challenged state within hours or days. However, exposure of animals or man to specific stimuli can induce delayed and long-lasting (weeks, months) alternation in stress responsive systems, resulting in a prolonged period of increased stress vulnerability. Immune stimuli are particularly powerful in eliciting such a stress vulnerable state. Various adaptive changes in the (neuro)biological substrate as seen during this stress vulnerable state also occur in depression, and may be causally related to the depressive symptoms that are often associated with infectious and inflammatory diseases.
Diabetic patients with acute coronary syndromes (ACSs) are at a high risk for subsequent cardiovascular events but derive, at the same time, greater benefit from evidence-based therapy than non-diabetic individuals. State-of-the-art anti-thrombotic therapy includes a triple anti-platelet combination - aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa receptor inhibitors - and unfractionated heparin or enoxaparin. For low- or medium-risk individuals, a treatment based on aspirin, clopidogrel and bivalirudin is a valuable alternative. Prasugrel, a new and more potent inhibitor of the platelet P2Y(12) receptor, has to be regarded as the most promising anti-thrombotic agent for diabetic patients with ACS. This agent may replace clopidogrel - and possibly GP IIb/IIIa inhibitors - in the future. In addition to aggressive anti-thrombotic therapy, diabetic patients should undergo systematic early invasive angiography if presenting with non-ST-segment elevation ACS, and immediate percutaneous coronary intervention if presenting with ST-segment elevation myocardial infarction. Indeed, the benefit derived from these strategies appears to be more pronounced in the diabetic population than in non-diabetic individuals. Despite the benefit, multiple surveys have demonstrated that, in the setting of ACS, diabetic patients receive evidence-based therapy less frequently than non-diabetic counterparts.
Acylethanolamides (AEs) are a group of lipids occurring in both plants and animals. The best-studied AEs are the endocannabinoid anandamide (AEA), the anti-inflammatory compound palmitoylethanolamide (PEA), and the potent anorexigenic molecule oleoylethanolamide (OEA). AEs are biosynthesized in the gastrointestinal tract, and their levels may change in response to noxious stimuli, food deprivation or diet-induced obesity. The biological actions of AEs within the gut are not limited to the modulation of food intake and energy balance. For example, AEs exert potential beneficial effects in the regulation of intestinal motility, secretion, inflammation and cellular proliferation. Molecular targets of AEs, which have been identified in the gastrointestinal tract, include cannabinoid CB(1) and CB(2) receptors (activated by AEA), transient receptor potential vanilloid type 1 (TRPV1, activated by AEA and OEA), the nuclear receptor peroxisome proliferators-activated receptor-alpha (PPAR-alpha, activated by OEA and, to a less extent, by PEA), and the orphan G-coupled receptors GPR119 (activated by OEA) and GPR55 (activated by PEA and, with lower potency, by AEA and OEA). Modulation of AE levels in the gut may provide new pharmacological strategies not only for the treatment of feeding disorders but also for the prevention or cure of widespread intestinal diseases such as inflammatory bowel disease and colon cancer.
Pituitary adenomas are classified by function as defined by clinical symptoms and signs of hormone hypersecretion with subsequent confirmation on immunohistochemical staining. However, positive immunostaining for pituitary cell types has been shown for clinically nonfunctioning adenomas, and this entity is classified as silent functioning adenoma. Most common in these subtypes include silent gonadotroph adenomas, silent corticotroph adenomas and silent somatotroph adenomas. Less commonly, silent prolactinomas and thyrotrophinomas are encountered. Appropriate classification of these adenomas may affect follow-up care after surgical resection. Some silent adenomas such as silent corticotroph adenomas follow a more aggressive course, necessitating closer surveillance. Furthermore, knowledge of the immunostaining characteristics of silent adenomas may determine postoperative medical therapy. This article reviews the incidence, clinical behavior, and pathologic features of clinically silent pituitary adenomas.
Pituitary adenomas are one of the most frequent intracranial tumors with a prevalence of clinically-apparent tumors close to 1:1000 of the general population. They are clinically significant because of hormone overproduction and/or tumor mass effects in addition to the need for neurosurgery, medical therapies and radiotherapy. The majority of pituitary adenomas have a sporadic origin with recognized genetic mutations seldom being found; somatotropinomas are an exception, presenting frequent somatic GNAS mutations. In this and other phenotypes, tumorigenesis could possibly be explained by altered function of genes implicated in cell cycle regulation, growth factors or their receptors, cell-signaling pathways, specific hormonal factors or other molecules with still unclear mechanisms of action. Genetic changes, such as allelic loss or gene amplification, and epigenetic changes, usually by promoter methylation, have been implicated in abnormal gene expression, but alternative mechanisms may be present. Familial cases of pituitary adenomas represent 5% of all pituitary tumors. MEN1 mutations cause multiple endocrine neoplasia type 1 (MEN1), while the Carney complex (CNC) is characterized by mutations in the protein kinase A regulatory subunit-1alpha (PRKAR1A) gene or changes in a locus at 2p16. Recently, a MEN1-like condition, MEN4, was found to be related to mutations in the CDKN1B gene. The clinical entity of familial isolated pituitary adenomas (FIPA) is characterized by genetic defects in the aryl hydrocarbon receptor interacting protein (AIP) gene in about 15% of all kindreds and 50% of homogenous somatotropinoma families. Identification of familial cases of pituitary adenomas is important as these tumors may be more aggressive than their sporadic counterparts.
Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of all pituitary adenomas. In the last years, the diagnosis has been facilitated by the routine use of ultra-sensitive TSH immunometric assays. Failure to recognise the presence of a TSHoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumour volume to further expand. The diagnosis mainly rests on dynamic testing, such as T3 suppression tests and TRH, which are useful in differentiating TSHomas from the syndromes of thyroid hormone resistance. The first therapeutical approach to TSHomas is the pituitary neurosurgery. The medical treatment of TSHomas mainly rests on the administration of somatostatin analogues, such as octreotide and lanreotide, which are effective in reducing TSH secretion in more than 90% of patients with consequent normalisation of FT4 and FT3 levels and restoration of the euthyroid state.
According to data derived from autopsy and radiological imaging series, pituitary tumours occur very commonly in the general population; however, most of these tumours are incidental findings with no obvious clinical impact. The historical data on the prevalence of pituitary adenomas in the clinical setting are scant and point to such tumours being relatively rare. Recent studies have shown that the prevalence of clinically relevant pituitary adenomas is 3-5 times higher than previously reported, which adds impetus to research into the aetiology of these tumours. Although the majority of pituitary adenomas are sporadic, approximately 5% of all cases occur in a familial setting and over half of these are due to Multiple Endocrine Neoplasia Type 1 (MEN-1) and Carney's Complex (CNC) disorders. Since the late 1990 s, we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes as a condition termed Familial Isolated Pituitary Adenomas (FIPAs). The clinical characteristics of the FIPAs vary from those sporadic pituitary adenomas, as patients with FIPAs have a younger age at diagnosis and larger tumours. About 15% of the FIPA patients have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that the FIPA may have a diverse genetic pathophysiology.
The pathogenesis of tumour formation in the anterior pituitary has been intensively studied, but the causative mechanisms involved in pituitary cell transformation and tumourigenesis remain elusive. Most pituitary tumours are sporadic, but some arise as a component of genetic syndromes such as the McCune-Albright syndrome, multiple endocrine neoplasia type 1, Carney complex and, the most recently described, a MEN1-like phenotype (MEN4) and pituitary adenoma predisposition syndromes. Some specific genes have been identified that predispose to pituitary neoplasia (GNAS, MEN1, PRKAR1A, CDKN1B and AIP), but these are rarely involved in the pathogenesis of sporadic tumours. Mutations of tumour suppressor genes or oncogenes, as seen in more common cancers, do not seem to play an important role in the great majority of pituitary adenomas. The pituitary tumour transforming gene (PTTG; securin) was the first transforming gene found to be highly expressed in pituitary tumour cells, and seems to play an important role in the process of oncogenesis. Many tumour suppressor genes, especially those involved in the regulation of the cell cycle, are under-expressed, most often by epigenetic modulation - usually promoter hypermethylation - but the regulator of these co-ordinated series of methylations is also unclear. Cell signalling abnormalities have been identified in pituitary tumours, but their genetic basis is unknown. Both Raf/MEK/ERK and PI3K/Akt/mTOR pathways are over-expressed and/or over-activated in pituitary tumours: these pathways share a common root, including initial activation related to the tyrosine kinase receptor, and we speculate that a change to these receptors or their relationship to membrane matrix-related proteins may be an early event in pituitary tumourigenesis.