Endocrine Development

Published by Karger
Vitamin D is important in skeletal development and in bone mineralization. The active form of vitamin D, 1α,25-dihydroxyvitamin D, [1,25(OH)2D], binds with high affinity to the vitamin D receptor (VDR), a member of the nuclear receptor family of transcription factors. Genetic mutations in the vitamin D receptor cause the rare genetic disease hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR). Children with HVDRR have rickets, hypocalcemia, hypophosphatemia, and secondary hyperparathyroidism. Some have total alopecia. A number of heterogeneous mutations have been identified in the VDR as the molecular cause of HVDRR. Mutations in DNA-binding domain inactivate the VDR by disrupting contact with VDREs in promoters of target genes. Mutations in the ligand-binding domain reduce the affinity of the VDR for 1,25(OH)2D, prevent the 1,25(OH)2D from binding to the VDR, inhibit RXR heterodimerization, or abolish coactivator interactions. Other types of mutations have also been found including nonsense mutations, splice site mutations, deletions, insertions, and duplications. Children with HVDRR have been successfully treated with intravenous calcium that bypasses the intestinal defect in calcium transport due to the lack of 1,25(OH)2D action on the mutant VDR.
Congenital hyperinsulinism (HI) of infancy, the most frequent cause of hypoglycaemia in young children, is a neuro-endocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormal pancreatic insulin secretion. This inappropriate secretion of insulin induces severe hypoglycaemias that require aggressive treatment to prevent the high risk of irreversible brain damage. Focal and diffuse forms of HI share a similar clinical presentation, but their treatment is dramatically different. Selective surgical resection can cure focal HI whilst diffuse forms require near-total pancreatectomy if resistant to medical treatment. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive method, technically difficult to perform, which requires general anaesthesia. The pancreas is one of the most heavily innervated peripheral organs in the body, and its functional imaging with positron emission tomography (PET) is difficult to perform, in part because of the vast number of physiological roles and cell types that characterize this organ. However, HI, as all neuro-endocrine diseases, is notable for the ability to take up amine precursors and to convert them into biogenic amines. Therefore, we have evaluated the use of PET with [18F]fluoro-L-DOPA, a precursor of catecholamines, to image the pancreas and distinguish focal from diffuse HI.
The disturbance of the hypothalamic-pituitary- adrenal axis characteristic of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is likely to affect brain development, yet neuroanatomic work is only beginning. Fetal hyperandrogenemia in 46, XX 21-OHD leads to masculinized brain organization and, consequently, at later stages of development, to masculinized gender-related behavior and cognitive function, including, although relatively uncommonly, gender identity. Genital masculinization as well as its surgical treatment has implications for social stigmatization and sexual functioning. CAH-associated electrolyte crises in infancy and later may result in severe cognitive impairment. Psychiatric disorders are somewhat increased, especially in patients with severe degrees of CAH.
Results show a significantly poorer performance in verbal working memory (measured with digit span from the WISC battery) in the DEX- treated group, while there are no between-group differences in general verbal reasoning ability (measured with the vocabulary from WISC). WISC=Wechsler Intelligence Scale for Children
Prenatal treatment of congenital adrenal hyperplasia (CAH) with dexamethasone (DEX) has been in use since the mid- 1980s. Its effectiveness for reducing virilization of external genitalia is well established. DEX treatment has to be started in the 6th-7th postmenstrual week and continued until the results of the prenatal diagnosis are available. Hence, the dilemma is that 7 out of 8 fetuses (boys and unaffected girls) are treated unnecessarily. Girls with CAH are treated until term. Accumulating evidence from animal studies and follow-up data has raised concerns regarding the long-term consequences of this controversial treatment. We have previously reported that direct neuropsychological assessment of children exposed to DEX and controls show normal full-scale IQ, learning and longterm memory. However, the children exposed to DEX during the first trimester had an impaired verbal working memory which was significantly associated with low self-perceived scholastic competence. In addition, the children showed increased self-rated social anxiety. The same cohort of children answered questions concerning friends, activities and gender-related behaviors. The results indicate less masculine and more neutral behavior in short-term DEX-exposed boys. These findings indicate that long-term follow-ups of this group of patients are of extreme importance and that future DEX treatment of CAH may be questioned. We therefore encourage additional studies on larger cohorts in order to draw more decisive conclusions about the safety of the treatment. Until then, it is important that the parents are thoroughly informed about the potential risks and uncertainties, as well as the benefits, of this treatment.
More than 95% of all cases of congenital adrenal hyperplasia are caused by deficiency of steroid 21-hydroxylase, an enzyme encoded by the CYP21A2 gene. The severity of the clinical symptoms varies according to the level of residual 21-hydroxylase activity. The CYP21A2 gene is located in the HLA class III region, as a component of so called RCCX modules containing homologous genes repeated in tandem. Misalignment followed by unequal crossing over as well as gene conversion events result in a high degree of variation in gene copy number as well as gene sequence in this genomic region. The presence of a highly homologous pseudogene, CYP21A1P, forms the basis for the relatively high incidence of 21- hydroxylase deficiency as deleterious sequences can be transferred from CYP21A1P to CYP21A2. Despite the complexity of the locus, safe approaches for genotyping are established, and genotype phenotype relationships have been documented making genotyping a valuable complement to biochemical investigations in the diagnostics of 21-hydroxylase deficiency. This is of particular importance in relation to family investigations and neonatal screening.
The understanding of phosphorus metabolism has expanded considerably over the last decade. Recent studies have identified a novel bone-kidney endocrine axis that maintains phosphate homeostasis. When phosphate is in excess, FGF-23 is secreted from bone and acts on the kidney to promote phosphate excretion into urine and to suppress vitamin D synthesis, thereby inducing negative phosphate balance. This review summarizes the role of the FGF-23 axis on phosphorus metabolism, and presents the clinical entities that arise from activation or inactivation of the FGF-23 axis.
During embryogenesis, the male external genitalia are formed by the action of the potent androgen, dihydrotestosterone (DHT). DHT is produced in human genital skin and prostate from testosterone via the action of 5alpha-reductase type 2. The biological relevance of this pathway to DHT is evidenced by patients with mutations in the gene encoding 5alpha-reductase type 2, which causes severely undermasculinized external genitalia in genetic males. In contrast, this paradigm of androgen physiology does not explain some clinical observations, such as the differences noted in the virilization of females with various congenital adrenal hyperplasias. An alternate pathway to DHT was elucidated in the tammar wallaby pouch young, and studies in knockout mice showed that this pathway uses 5alpha-reductase type 1 to convert 17-hydroxyprogesterone to 5alpha-reduced androgen precursors. Flux via the alternate or 'backdoor' pathway has been implicated in human diseases such as P450 oxidoreductase deficiency, polycystic ovarian disease, and congenital adrenal hyperplasia. A better understanding of the 5alpha-reduced or 'backdoor'pathway to DHT in human disorders of androgen excess will provide pharmacotherapy opportunities to effectively treat androgen excess in females.
Timeline of the development of the posterior pituitary neurone. SIM1, ARNT2, OTP and BRN2 are genes involved in the cascade of transcription factors. PVN = Paraventricular nuclei; SON = supraoptic nuclei: SS = synthesizing somatostatin; TRH = thyrotropin-releasing hormone; CRH = corticotrophin-releasing hormone; AVP = arginine vasopressin; OT = oxytocin. With permission.  
Tree diagram showing the two main categories of developmental anomalies of the posterior pituitary gland.  
a Normal pituitary gland appearance on sagittal T 1 -weighted images. The posterior pituitary hyperintensity (PP, arrowhead), anterior pituitary lobe (AP, thick arrow), pituitary stalk (PS, thin arrow) and median eminence (ME) are clearly visible. b Case with MPHD, small pituitary sella, anterior pituitary hypoplasia (thick arrow), absent pituitary stalk and ectopic posterior lobe at the of the median eminence (arrowhead). c Case with MPHD, small pituitary sella, anterior pituitary hypoplasia (thick arrow), and ectopic posterior lobe at the distal end (arrowhead) of the hypoplastic pituitary stalk (thin arrow). d Case with isolated GHD, small pituitary sella, anterior pituitary hypoplasia and ectopic posterior lobe within the middle third (arrowhead) of pituitary stalk. e Case with isolated GHD, small pituitary sella, anterior pituitary hypoplasia and ectopic posterior lobe at the distal end (arrowhead) of pituitary stalk. f Case 7 with evolving pituitary hormone deficiency, small pituitary sella, anterior pituitary hypoplasia and ectopic posterior lobe extended (arrowhead) within the pituitary stalk.  
Small arrows showing ectopic posterior pituitary (EPP) in figures (a) and (b). Long arrow shows Arnold-Chiari I malformation in figure b. Arrows indicate syringomyelia in figure c.  
Different sizes of ectopic posterior pituitary (EPP) and anterior pituitary (AP) are represented in both sagittal (a, c, e) and coronal (b, d, f) T 1 -weighted MRI scans. a, b patient with MPHD. Thick arrow = small EPP; thin arrow = severe AP hypoplasia. c, d Patient with GH deficiency. Thick arrow = Large EPP; thin arrow = mild AP hypoplasia. e, f Patient with GH deficiency. Thick arrow = XXL EPP; thin arrow = borderline AP size.  
While the molecular mechanisms of anterior pituitary development are now better understood than in the past, both in animals and in humans, little is known about the mechanisms regulating posterior pituitary development. The posterior pituitary gland is formed by the evagination of neural tissue from the floor of the third ventricle. It consists of the distal axons of the hypothalamic magnocellular neurones that shape the neurohypophysis. After its downward migration, it is encapsulated together with the ascending ectodermal cells of Rathke's pouch which form the anterior pituitary. By the end of the first trimester, this development is completed and vasopressin and oxytocin can be detected in neurohypophyseal tissue. Abnormal posterior pituitary migration such as the ectopic posterior pituitary lobe appearing at the level of median eminence or along the pituitary stalk have been reported in idiopathic GH deficiency or in subjects with HESX1, LHX4 and SOX3 gene mutations. Another intriguing feature of abnormal posterior pituitary development involves genetic forms of posterior pituitary neurodegeneration that have been reported in autosomal-dominant central diabetes insipidus and Wolfram disease. Defining the phenotype of the posterior pituitary gland can have significant clinical implications for management and counseling, as well as providing considerable insight into normal and abnormal mechanisms of posterior pituitary development in humans.
2005– 2008 guidelines for medical care of children evaluated for suspected sexual abuse: consensus statement and revision of the former 'Adams classification' (detailed references in the original article: [50]) 
Medical involvement in the diagnosis and treatment of child sexual abuse (CSA) has a well-defined role within a multidisciplinary concept. Due to the increasingly high rate of normal anogenital findings in victims of CSA, forensic aspects are of limited value in establishing the diagnosis. In selected cases however, medical findings may play an important role in corroborating a child's history. Correct evaluation of normal and abnormal findings, normal variations and several differential diagnoses requires sound knowledge in pediatric gynecology. In some cases, physical consequences of CSA (injuries, infections, and pregnancy) need to be diagnosed and treated (prevented) accordingly. The majority of abused children have an altered and distorted body image. It is of paramount importance to reassure the child that its body is normal, physically undamaged, intact or that it will heal ('primary therapeutic aspect of the medical examination'). Thus, the medical examination has an enormous potential to incorporate a therapeutic message into the diagnostic procedure if performed in a qualified and sensitive manner. By communicating with the psychosocial und jurisdictional systems, physicians may initiate proper child protection and therapy. Therefore, medical evaluation of sexually abused children must always be integrated into a multiprofessional concept of child protection.
Inflicted non-accidental skeletal injuries form a small but important part of the spectrum of child abuse, with the majority of skeletal injuries occurring in children under 2 years of age. Radiology plays a vital role in the detection and evaluation of these skeletal injuries. A thorough detailed radiological evaluation should be undertaken in order to investigate appropriately a child for suspected inflicted non-accidental injury. This is to detect accurately, and possibly date, any injuries, exclude normal variants of growth which may mimic fractures and possibly to diagnose any underlying metabolic or genetic disorder of the bone which may predispose a child to fracturing. Any fracture may be the result of an inflicted injury or accidental event. It is therefore appropriate that any fracture that is identified is correlated with relevant appropriate clinical history. Certain injuries, such as rib or metaphyseal fractures, require a more specific method of causation and therefore have a higher degree of suspicion of being the result of an inflicted injury than other fracture types, such as skull and clavicular fractures, which are relatively non-specific in their mechanism of causation. In all cases, correlation with the clinical history is mandatory. While radiology does play an important role in the dating of injuries, the dating of fractures from the radiological findings is difficult and imprecise.
Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications.
Mutations in the MRAP. Cartoon depicting the protein structure of the single transmembrane domain MRAP protein. Mutations are represented at either protein level (denoted p.) or cDNA level (denoted c.). With the exception of p.Y59D and p.V26A, the two missense mutations, all the mutations will lead to early truncation of the protein and absence of the MC2R interacting transmembrane domain.
Mutations in the STAR. Gene structure of STAR with mutations in each exon indicated in boxes. The mutations are described at either protein level (denoted p.) or cDNA level (denoted c.). Numbering is based on that given in the original manuscripts describing the mutations. Asterisk indicates ‘mild’STAR mutations presenting with a FGD-like phenotype.
Cholesterol delivery and mitochondrial steroidogenesis. Free cholesterol is delivered to the outer mitochondrial membrane (OMM) by StarD4 and transferred to the inner mitochondrial membrane (IMM) by STAR, where steroidogenesis begins. The first step of cortisol synthesis is the conversion of cholesterol to pregnenolone by CYP11A1 (side chain cleavage enzyme), and the last step is the conversion of 11-deoxycortisol to cortisol by CYP11B1; the steps in between occur outside the mitochondrion.
Mutations in NNT. Cartoon depicting gene structure of NNT and the mutations described to date. Mutations are represented at either protein level (denoted p.) or cDNA level (denoted c.).
ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses.
Effect of neurotransmitters and other neuromediators on CRH/ACTH secretion 
The hypothalamic-pituitary-adrenal (HPA) axis is a major integrated system that maintains body homeostasis by regulating the neuroendocrine and sympathetic nervous systems and modulating immune function. It is well established that the central nervous system (CNS) integrates responses to different stimuli secreting a specific corticotropin-releasing hormone (CRH) and vasopressin (AVP). In turn, they stimulate the release of ACTH, which induces steroidogenesis in the adrenal gland. The HPA axis is regulated by diurnal rhythms and negative feedback by corticosteroids. Many neurotransmitters and neuropeptides are responsible for the modulation of CRH and AVP neurons. In addition to synthetic glucocorticoids that inhibit the HPA axis, GABA agonists, opioid peptides and endocannabinoids can inhibit cortisol secretion. On the contrary, serotonin, norepinephrine, dopamine, acetylcholine, ghrelin, angiotensin II and different cytokines can stimulate it. It follows that a number of neuroactive drugs, acting as agonists or antagonists on several brain neurotransmitter or neuropeptide receptors, can influence ACTH/cortisol secretion thereby interfering with clinical testing of the functionality of the HPA axis.
Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of the GR. The molecular mechanisms that regulate glucocorticoid action highlight the dynamic nature of hormone signaling and provide novel insights into genomic glucocorticoid actions and glucocorticoid sensitivity. Although glucocorticoids are highly effective for therapeutic purposes, long-term and/or high-dose glucocorticoid administration often leads to reduced glucocorticoid sensitivity or resistance. Here, we summarize our current understanding of the mechanisms that modulate glucocorticoid sensitivity and resistance with a focus on GR-mediated signaling.
Besides its growth hormone-releasing effect, ghrelin has been demonstrated to influence other hormonal systems, such as the hypothalamo-pituitary-adrenal axis, prolactin secretion, the thyroid axis as well as the gonadal axis. Ghrelin and its analogues stimulate the hypothalamo-pituitary-adrenal axis independent of the pituitary, via the hypothalamus, involving both corticotrophin-releasing hormone, arginine-vasopressin and neuropeptide Y stimulation. In adrenocortocotropic hormone (ACTH)-secreting tumors, the ghrelin receptor is pathologically expressed, thus accounting for especially high ACTH and cortisol responses to ghrelin and GH secretagogues in patients with Cushing's disease. Ghrelin stimulates prolactin release most probably from the somatomammotroph cells of the pituitary gland. The effect of ghrelin on the pituitary regulation of the thyroid axis is controversial and its role in the physiological control of thyroid function is still matter of investigation. On the other hand, ghrelin has been reported to exert an inhibitory effect on follicle-stimulating hormone and, in particular, on luteinizing hormone, probably via an inhibitory effect exerted at the hypothalamic level on gonadotropin-releasing hormone secretion.
The acylated form of ghrelin (GRLN) has been discovered as the natural ligand of the GH secretagogue (GHS) receptor-1a (GHS-R1a). This peptide, whose acylation is performed by a specific octanoyl-transferase, is predominantly produced by the stomach, although expressed by many other endocrine and nonendocrine, peripheral and central tissues. Also GHS-R1a shows wide distribution, being distributed in several central and peripheral tissues. GRLN displays strong GH-releasing activity but its action is not specific for GH exhibiting other neuroendocrine activities such as stimulation of PRL and ACTH and inhibition of LH. GRLN is now mostly recognized as a potent orexigenic factor stimulating food intake and modulating energy expenditure. At the peripheral level, GRLN modulates gastrointestinal motility and secretion and also exerts cardiovascular actions. Mostly, at the peripheral level, GRLN exerts probably its major physiological action regulating glucose and lipid metabolism. In fact, GRLN in its acylated form has a diabetogenic action while in its non-acylated form it has a favorable influence on glucose, lipid metabolism and insulin sensitivity as well as the inhibition of lipolysis. GRLN receptors have been well demonstrated either in the endocrine pancreas or the adipose tissue; at these levels there are receptors that bind GRLN independently of its acylation (therefore a non-GHS-R1a, still undefined receptor). In all, the products of the GRLN gene, i.e. acylated and nonacylated GRLN, as well as obestatin, play a major role in regulating peripheral metabolism and it is not by chance that their secretion is mostly under metabolic regulation.
Unacylated ghrelin (UAG), or des-acyl ghrelin, is slowly fighting its way up into the field of interest that studies preproghrelin gene-encoded peptides. Long considered to be an inert degradation product of (acylated) ghrelin (AG), UAG nowadays emerges as an important hormone, separate from the other proghrelin-derived peptides, AG and obestatin. UAG appears to have its own receptor, and it can share this receptor with AG, under experimental conditions at least. An increasing number of studies suggest that UAG can act as a potent functional inhibitor of ghrelin. It can even strongly suppress ghrelin levels in obese human diabetic subjects. Moreover, UAG can improve postprandial glycemia, especially in those subjects in whom preprandial acylated ghrelin levels are high, which makes UAG, or UAG analogs strong potential candidates for the development of drugs for the treatment of metabolic disorders or other conditions in which elevated AG/UAG ratios occur, such as diabetes, obesity and Prader-Willi syndrome.
Ghrelin is a gut hormone with potent orexigenic and growth hormone release stimulatory effects, and is the first known endogenous ligand of the growth hormone secretagogue receptor. A notable feature of ghrelin is that it carries an acyl group, in most cases an octanoyl group, in the third serine. While it has been shown that the acylation is critical for the majority of ghrelin functions, the mechanisms of acylation of ghrelin remained poorly understood. In 2008, it was discovered that ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylating ghrelin. GOAT is highly conserved from zebrafish to humans. It is most abundant in the stomach and pancreas. GOAT mRNA expression is regulated by energy balance, being upregulated by energy restriction and downregulated by energy abundance. GOAT attenuation using synthetic inhibitors enhances insulin secretion and reduces body weight. GOAT inhibitors are currently being developed for the treatment of metabolic disorders. In addition to its ghrelin mediated effects, GOAT is also known to directly regulate bile acid secretion. The discovery of GOAT helped to redefine the ghrelin research field and enabled the development of another target molecule for potential therapies aimed to prevent/treat diabetes and obesity.
Primary adrenocortical insufficiency, or Addison's disease (AD), results from an adrenal cortex hypofunction/dysfunction with a deficient production of glucocorticoids, mineralocorticoids and androgens, and with high levels of both ACTH and plasma renin activity. The prevalence of AD is 110-144 cases per million population in the developed countries. Autoimmune AD is the most frequent etiological form in adult patients, accounting for about 80% of cases, followed by post-tuberculosis AD in 10-15%, the remaining 5% being cases are due to vascular, neoplastic or rare genetic forms. Congenital adrenal hyperplasia is the most frequent form of AD in children and accounts for 72% of cases, whereas autoimmune AD is seen in around 10-15% of cases. The markers of autoimmune AD are adrenal cortex (ACA) or 21-hydroxylase autoantibodies (21-OHAbs) and they are present at diagnosis in more than 90% of cases. In autoimmune AD, the adrenal cortex is infiltrated by lymphocytes and plasma cells and the glands are sclerotic and reduced in volume. Autoimmune AD occurs mainly in middle-aged females, alone or associated with other (clinical, subclinical or potential) autoimmune diseases, giving rise to various forms of autoimmune polyglandular syndrome (type 1, 2 or 4). Replacement therapy with gluco-and mineralocorticoids is life-saving for patients with chronic adrenal insufficiency.
Pituitary adenomas are one of the most frequent intracranial tumors. Usually, they are benign but are of great clinical significance because of tumor compression syndrome and hormone overproduction. The interest in this pathology is increasing, particularly after some recent reports on their prevalence that proved to be 3-5 times more than previously estimated. Pituitary tumors arise in a sporadic setting and rarely as part of hereditary genetic syndromes. Such rare hereditary conditions like MEN1, Carney complex and McCune-Albright syndrome give significant insight into pituitary tumorigenesis. Newer genes associated pituitary tumor development include CDKN1B (MEN4) and AIP, the latter of which is involved in the pathophysiology of 15% of FIPA kindreds. The number of genes involved in pituitary tumorigenesis is progressively increasing and the possible mechanisms of action include signal transduction pathways, cell cycle regulators, growth factors, chromosome instability and others. Nevertheless, in the majority of sporadic adenomas, the primary genetic defect remains unknown. Furthermore, there is not a well established relationship between the genotype and its influence on the protein expression, ligand-receptor interaction, tumor growth or hormone hyperproduction. Further studies should evaluate the clinical significance of genetic alterations and their implications for existing and new therapeutic options.
Effects of the ghrelin gene-derived peptides in the pancreatic β-cell and the adipocyte. Acylated ghrelin (blue), unacylated ghrelin (red) and obestatin (green) exert both similar and opposed actions. Only the most important effects are indicated and in some cases, such as gene expression (regulation of genes involved in β-cell survival, differentiation and function, left panel), data are obtained from studies performed with only one of the three peptides.
The ghrelin system comprises acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin, besides the receptor for AG, the growth hormone (GH) secretagogue receptor type 1a (GHS-R1a), and the enzyme-promoting ghrelin acylation, ghrelin O-acyltransferase (GOAT). The ghrelin peptides exert a variety of biological actions, including regulation of energy homeostasis and glucose metabolism, as well as survival and proliferative effects in different cell types. Besides the stomach, its main site of production, ghrelin is expressed in pancreatic islets, where it represents an independent islet cell population. AG exerts insulinostatic actions, UAG has been shown to oppose the AG inhibitory effects on insulin secretion, and obestatin has demonstrated insulinotropic activities. Although differences exist in the regulation of glucose homeostasis, all peptides display survival and antiapoptotic actions in pancreatic β-cells, preserving β-cell mass and function both in vitro and in vivo. The ghrelin system is also expressed in adipose tissue, and ghrelin effects have been demonstrated in both white and brown adipocytes. Indeed, AG, UAG and obestatin promote adipogenesis and glucose uptake, and inhibit adipocyte lipolysis. Interestingly, despite similar effects at the cellular level, results from ghrelin, GHS-R and GOAT knockout mice have indicated that AG display diabetogenic effects in vivo. Conversely, UAG and obestatin positively regulate glucose metabolism, and a new role has been recently proposed for obestatin on adipocyte function and insulin sensitivity.
In mammals, the adipose organ is composed of white adipocytes (primary site in energy storage) and of brown adipocytes (specialized in thermogenesis). Adipocytes arise from mesenchymal stem cells (MSCs) by a sequential pathway of differentiation. MSCs develop either from ectoderm or mesoderm and commit into different undifferentiated precursors, which upon the expression of key transcription factors enter a differentiation program to acquire their specific functions. When triggered by appropriate developmental cues, MSCs become committed to the adipocyte lineage. White adipocytes differentiate from various types of vascular cell types, probably located within the white adipose tissue itself. Brown adipocytes arise from myogenic precursors. The differentiation between white adipocyte and brown adipocyte lineages occurs in the earliest steps of the fetal development, and both phenotypes are acquired independently. A better knowledge of these differentiation pathways allows new therapeutic strategies for reconstruction of damaged conjunctive tissues and for the control or prevention of risks associated with obesity in humans.
In addition to diabetes and cardiovascular diseases, epidemiological evidence demonstrates that people who are obese or overweight are at increased risk of developing cancer - colon, breast (in postmenopausal women), endometrial or kidney cancer being among the most frequent. In addition to the increase in tumor occurrence, obesity also affects tumor prognosis, especially in breast and prostate cancers. In breast cancer, obesity is associated with reduced survival and increased recurrence independent of menopausal status. Host factors seem to contribute to the occurrence of tumors exhibiting an aggressive biology defined by advanced stages and high grade. Mature adipocytes are part of the breast cancer tissue and as highly endocrine cells susceptible to profoundly modify breast cancer cell behavior. Tumor progression has recently been recognized as the product of an evolving crosstalk between tumor cells and the surrounding 'normal' cells. We propose that such a bidirectional crosstalk exists between breast cancer cells and tumor-surrounding adipocytes, and that the tumor-modified adipocytes (or cancer-associated adipocytes) are key actors in tumor progression. The positive contribution of cancer-associated adipocytes into tumor progression might be amplified in obese women and explains at least in part the poor prognosis observed in this subset of patients.
The discovery of leptin has clearly demonstrated a relationship between body fat and the neuroendocrine axis since leptin influences appetite and the reproductive axis. Since adipose tissue is a primary source of leptin, adipose tissue is no longer considered as simply a depot to store fat. Recent findings demonstrate that numerous other genes, i.e. neuropeptides, interleukins and other cytokines and biologically active substances such as leptin and insulin-like growth factors I and II, are also produced by adipose tissue, which could influence appetite and the reproductive axis. Targets of leptin in the hypothalamus include neuropeptide Y, proopiomelanocortin and kisspeptin. Transsynaptic connection of hypothalamic neurons to porcine adipose tissue may result in a direct influence of the hypothalamus on adipose tissue function. Nutritional signals such as leptin are detected by the central nervous system and translated by the neuroendocrine system into signals which ultimately regulates luteinizing hormone secretion. Furthermore, leptin directly affects gonadotropin-releasing hormone release from the hypothalamus, luteinizing hormone from the pituitary gland and ovarian follicular steroidogenesis. Although leptin is identified as a putative signal that links metabolic status and neuroendocrine control of reproduction, other adipocyte protein products may play key roles in regulating the reproductive axisin the pig.
Over the last 15 years a number of long-term health risks associated with reduced fetal growth have been identified, including cardiovascular diseases, hypertension, dyslipidemia, or type 2 diabetes. A common feature of these conditions is insulin resistance, which is thought to play a pathogenic role. However, despite abundant data in the literature, it is still difficult to trace the pathway by which fetal events, environmental or not, may lead to the increased morbidity later in life. To explain this association, several hypotheses have been proposed pointing to the role of either a detrimental fetal environment or a genetic susceptibility or an interaction between the two and of the particular dynamic changes in adiposity that occur during catch-up growth. The relative impact of early postnatal events in relation to fetal growth has to be considered for designing health policy strategies for early interventions aimed at decreasing the diseases risk throughout life.
There are more and more data supporting the importance of nervous regulation of both white and brown adipose tissue mass. This short paper will review the different physiological parameters which are regulated such as metabolism (lipolysis and thermogeneis), secretory activity (leptin and other adipokines) but also to plasticity of adipose tissues (proliferation differentiation and apoptosis). The sensory innervation of white adipose issue and its putative role will be also described. Altogether these results showed the presence of a neural feedback loop between adipose tissues and the brain which plays a major role in the regulation of energy homeostasis and has been shown to be altered in physiologic as well as in metabolic pathologies.
Polycystic ovary syndrome (PCOS) is a prevalent cause of menstrual disorders, acne and hirsutism presenting during adolescence. In the majority of cases, a familial trait is obvious but the offending genes have yet to be identified. However, much of the pathophysiology of the syndrome causing the overproduction of ovarian androgens is now becoming clearer. The early diagnostic signs are often mistakenly dismissed as normal changes of adolescence but it is important to make an early diagnosis in order to save the adolescent from the early and late stigmata of the syndrome. The avoidance of overweight, frank obesity and the consequential exaggeration of symptoms by the associated insulin resistance is of prime importance as hyperinsulinemia plays a key role in the pathogenesis. Anti-androgens are the most widely used medication and, in combination with estrogen, are capable of restoring menstrual regularity and reducing the symptoms of acne and hirsutism, so important for the improvement of the disturbing psychosocial effect that they may play at this age. The use of metformin, an insulin sensitizer, for affected adolescents is the topic of a presently heated debate.
Eating disorders (EDs) are conditions which are becoming more and more widespread among adolescents and they often lead them to seek the opinion of a professional health caregiver, including gynecologists and pediatricians. EDs, and particularly anorexia nervosa (AN), are usually classified as psychological or psychiatric disorders, but they may have major somatic implications and complications as osteoporosis, nutritional deficiencies, cerebral atrophy, cardiac and metabolic disorders. A key issue in the management is prevention or reduction of both the serious somatic consequences and the important mental health consequences (e.g. depression, psychosocial withdrawal, phobia and suicide), integrating different perspectives (psychological or psychiatric - individual and familial -, genetic, nutritional, pediatric, gynecological). Adolescence is a critical period for the onset of EDs though they may also involve younger children. In this case, the consequences on the development (height, weight, puberty) can also be significant. In this review, we will focus on eating disorders in adolescent girls with an emphasis on AN. We describe variations in ED characteristics and their management depending on age at occurrence. A possible ED should be considered by pediatricians consulted about delayed female growth and puberty as well as gynecologists in patients with primary or secondary amenorrhea or infertility.
Puberty is characterized by a series a hormonal events leading to the attainment of adult reproductive capacity. Clinical manifestations of the pubertal processes include breast development, pubic hair development, menarche and regular menstrual bleedings. Abnormal pubertal development includes a spectrum of disorders such as premature thelarche, premature adrenarche, central and peripheral precocious puberty, adolescent polycystic ovarian syndrome, functional ovarian hyperandrogenism, late-onset congenital adrenal hyperplasia, primary and secondary amenorrhea, and premature ovarian insufficiency. Diagnosis of these reproductive disorders includes biochemical as well as clinical evaluation. The biochemical evaluation of reproductive function includes measurement of basal reproductive hormone levels and dynamic pituitary or adrenal hormone testing. Correct interpretation of such test results requires detailed knowledge on the normal maturational changes in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes. Changes in basal reproductive hormone levels in infancy, childhood and adolescence as well as the GnRH and ACTH test procedures in girls and adolescents are described in this chapter.
The achievement of final adult height occurs much earlier than the acquisition of peak bone mass and muscle strength in both genders, males achieving these milestones later than females. This transition period is particularly challenging in adolescents that were treated with GH during childhood. A high percentage of these adolescents in transition are no longer considered GH-deficient at the completion of their linear growth, making it necessary to retest GH reserves using potent secretagogues (such as insulin tolerance tests (ITT) or arginine/GHRH) and more stringent cutoff peaks (<6 ng/ml in this age group for ITT for example) to establish the correct diagnosis of GH deficiency. This is especially important in those with idiopathic isolated GH deficiency. Who, how and when to test are critical so that patients who are truly GH-deficient can be selected for lifelong therapy while others are spared. Data on the efficacy of GH in these patients have shown mixed results (some positive changes, others minimal or no improvement) on body composition and bone mineral density (BMD) accrual, e.g., most likely due to the differences in the length of time that patients have been off GH in the published studies. In those persistently deficient with abnormally low BMD (i.e. <-2 SD), low IGF-1 and abnormal body composition (high % body fat), GH should be continued starting at doses of 12.5 microg/kg x day and IGF-1 measured periodically and kept in the mid to upper limits of normal (within +1 SD). A repeat DEXA scan for BMD and body composition assessment a year after initiation of treatment is useful to guide therapy. GH is no substitute for healthy eating, weight control and regular exercise in diminishing cardiovascular risk, but these subjects should likely be treated at least through their mid-20s when peak BMD and muscle strength are achieved, at which time reassessment of the lifelong need for GH can be made in the idiopathic GH-deficient group. Those with multiple pituitary hormone deficiencies on the other hand should be replaced indefinitely with GH. The treatment of the GH-deficient adolescent in transition should be individualized.
Culturally sensitive gynecologic care means rendering gynecologic care taking into account adolescents' needs, problems and feelings, as seen by adolescents themselves. Adolescence is a period of turmoil, where limits are being tested and risks taken. A certain degree of rebellion is necessary and normal. In contemporary societies, risk-taking behaviors seem to outnumber any previous historical period. Antagonistic depictions of 'two worlds', transforms the question into one between a culture and a counterculture. Sometimes, the perspectives are exaggerated by attitudes of superiority, leading to inadequate or punitive practices. Health providers need to confront their own prejudices, so as to understand that in their role as health workers, what adolescents ask for is help to cope with their problems in the fields that professionals are qualified for, but not to behave as policemen, judges or priests. Adolescents also need help to overcome resistance to formal environments. In order to achieve success, they have to have the opportunity to be heard and to participate in tailoring programs. These undertakings should be aimed at contributing to health promotion, encouraging self-care and reaffirming confidence in adolescents' responsibility, while generating trust in health services and professionals.
Sonography is a versatile diagnostic imaging modality which uses acoustical energy. In the pediatric patient, it can be used in several areas of the body, particularly within the abdomen and pelvis. Over the last several years, the use of sonography for the evaluation of pediatric disorders has become more widespread for several reasons. These include the non-ionizing character of sonography relative to the radiographic techniques and the enhanced soft tissue detail now afforded by most real-time ultrasound scanners. The increased use and availability of real-time scanners has also contributed to more extensive use of sonography. Since children have very little perivisceral fat, they are almost ideal subjects for ultrasound scanning because high-frequency transducers which afford the best possible resolution can be used. The lack of irradiation allows repeat examinations to be performed without fear of untoward bioeffects due to radiation. The role of sonography in the evaluation of pediatric gynecologic disorders will no doubt continue to expand, particularly as more pediatricians, gynecologists and radiologists become more familiar with its applications in pediatric gynecology.
Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of 'free' IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of 'free' IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.
During puberty, the acquisition of skeletal mass and areal bone mineral density (BMD) mainly reflects an increase in bone size (length and perimeters) and not true volumetric BMD. Sexual dimorphism in bone mass and areal BMD is also explained by differences in bone size (longer and wider bones in males) and not by differences in volumetric BMD. Androgens stimulate skeletal growth by activation of the androgen receptor, whereas estrogens (following aromatization of androgens and stimulation of estrogen receptors) have a biphasic effect on skeletal growth during puberty. Recent evidence from clinical cases has shown that many of the growth-promoting effects of the sex steroids are mediated through estrogens rather than androgens. In addition, skeletal maturation and epiphyseal fusion are also estrogen-dependent in both sexes. Nevertheless, independent actions of androgens in these processes also occur. Both sex steroids maintain volumetric BMD during puberty. Androgens interact with the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis neonatally, resulting in a sexual dimorphic GH pattern during puberty, whereas estrogens stimulate GH and hereby IGF-I in both sexes. Hypogonadism in adolescents impairs not only bone size but also maintenance of volumetric BMD, hereby severely reducing peak areal BMD. Delayed puberty in boys and Turner's syndrome in women impair both bone length and size, reducing areal BMD. Whether volumetric BMD is also reduced and whether fracture risk is increased in these conditions remains controversial. Replacing sex steroids according to a biphasic pattern (starting at low doses and ending at high-normal doses) seems the safest approach to reach targeted height and to optimize bone development.
Sexual health for adolescents is based on three components: recognizing sexual rights, sexuality education and counseling, and confidential high-quality services. Contraception needs to include prevention of both STIs and pregnancy. The main options for adolescents are condoms backed-up by emergency contraception; and hormonal contraceptives in a longer, mutually monogamous relationship. Condoms and hormonal contraception together can be well recommended for adolescents. Condom use should not be stopped before it is reasonably certain that the partner is STI-negative. Other alternatives can be considered in special cases. Improved contraceptive methods do not automatically lead to reduced numbers of adolescent abortions. The prevention of unintended adolescent pregnancies requires four elements: a desire to use protection, a good contraceptive method, ability to obtain the contraceptive method, and ability to use it. All these components are important, and if one is missing contraception will fail. In the developed countries, we have good contraceptive methods, but improvements are still needed in the other components. When adolescent sexuality is not condemned but sexuality education and sexual health services instead are provided, it is possible to profoundly improve adolescent sexual health with comparatively small costs. Each year new groups of young people mature, requiring new efforts.
Primary dysmenorrhea, which affects from 43 to 91% of adolescent girls, is defined as painful uterine cramps that precede and accompany menses. Primary dysmenorrhea is related to an overproduction of uterine prostaglandins which induces myometrium hypercontractility and arterioral vasoconstriction, both involved in painful menstrual cramps. In addition, headache, nausea, asthenia, irritability and school absenteeism are frequently reported and need to be quantified through a clinical score. Despite its relevant impact on adolescent quality of life and availability of efficacious medication such as non-steroidal anti-inflammatory drugs, only 15% of affected adolescents consult a physician for this pain syndrome. Pediatricians and gynecologists should thus be more actively involved in the diagnosis and treatment of adolescent primary dysmenorrhea.
Pediatric gynecological examination is very simple, but usually unrecognized by physicians without a specific experience in pediatric gynecology. It is always necessary and most of the time sufficient in children and adolescents consulting for gynecological complaints, endocrine problems, or sexual abuse. However, accurate evidence-based data on its normality is poor in the literature, because of bias represented by the inclusion of abused patients in these studies. Our aim was to describe the preparation to a full gynecological examination, the adequate positions, and the sequence and technique required for a well-accepted and nontraumatic clinical examination. Normal findings are described depending on the age of the patient (child, newborn, adolescent), and are based on evidence from the literature. Indications for vaginoscopy and bacterial sampling are discussed according to the age of the patient. The most important factors in the achievement of a full gynecological examination and a trusting patient-physician relationship are a good anatomical and physiological knowledge of the genital system in children, and the learning of nonaggressive examination technical skills associated with good communication skills. Clinical examination is always necessary and most of the time is sufficient together with the medical history to diagnose and treat the child's gynecological problems. Evidence-based data on normal genital findings is poor in the literature, because many studies include abused children or present bias in the methods of recruitment and assessment of normal girls [1].
Chronic pelvic pain occurs commonly in the adolescent and can be a diagnostic and therapeutic challenge for the clinician, the adolescent, and her family. Defined as lower quadrant or lower abdominal pain lasting 3-6 months or longer, chronic pelvic pain can lead to missed school and activities, decreased functioning, and decreased quality of life in the adolescent. Both the primary care clinician and the pediatric gynecologist need to be aware of the most common causes of chronic pelvic pain in the adolescent, including surgical and nonsurgical, gynecologic versus other pathology including the psychosomatic, and the role of the mind in control of somatic pain in the adolescent. Adding to this complexity is the standard adolescent sense of invulnerability; a knowledge of adolescent development remains essential to the delivery of appropriate gynecologic care for this age group. Education and communication with both the adolescent and her family requires sensitivity, especially in cultures where adolescent sexuality is taboo or discouraged. This chapter will discuss the developmental stages of adolescence and how that impacts care of the patient with chronic pelvic pain at the varying ages, the issue of confidentiality when obtaining a sexual history on the adolescent, and etiologies of chronic pelvic pain specific to the adolescent, including gynecologic and nongynecologic causes. Diagnostic and treatment considerations for chronic pelvic pain in the adolescent will also be addressed.
When the symptoms of hyperandrogenism are mild in an adolescent girl, it is difficult to establish whether they are related to the physiological androgenization of puberty or to an incipient disease. The most frequent etiology is the polycystic ovary syndrome (PCOS). Its diagnosis is defined in adult women by precise criteria which need to be adapted to the particular case of the adolescent girl. Nonclassic adrenal hyperplasia is the main differential diagnosis to PCOS. Although much less frequent, other etiologies of peripubertal hyperandrogenism such as adrenal or ovarian tumors or Cushing's disease must be considered by analyzing the rapidity of installation and intensity of hyperandrogenic symptoms and by a systematic hormonal work-up. In addition to etiologic measures, the treatment consists of administration of an anti-androgen, mainly cyproterone acetate. In the case of PCOS, the patient needs to be educated regarding the metabolic risks.
The extended contents of this second edition reflect the growing spectrum of topics in pediatric and adolescent gynecology. Like its predecessor, this book addresses the most common gynecological problems encountered in childhood medicine, including endocrinological and surgical aspects. New chapters place particular emphasis on an update of technological aspects such as ultrasound, molecular genetics, surgery in sex disorders and new problems encountered in reproductive medicine. The book opens with a comprehensive description of the background of infant and adolescent gynecology and diagnostic tools. Several chapters are devoted to the various pathologies encountered in prepubertal and adolescent girls. Contemporary social issues such as sexual abuse, sexually transmitted diseases, contraception for teenagers and teenage pregnancy are also discussed in detail. Presenting a clear plan for clinical management and treatment of frequently encountered problems in prepubertal and adolescent girls, this book should be read by pediatricians, endocrinologists, gynecologists and family practitioners. © 2012 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland). All rights reserved.
Top-cited authors
Sylvia f boj
  • Hubrecht Organoid Technology (HUB)
Carina Cardalda
  • IDIBAPS August Pi i Sunyer Biomedical Research Institute
Miguel Angel Maestro
  • Centro de Investigación Biomédica Esther Koplowitz
Alan J Conley
  • University of California, Davis
Ken Darzy
  • The Queen Elizabeth Hospital