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Cortisol levels in term and preterm infants

After birth biologically active cortisol predominates over cortisone in the circulation, although not to the same extent as adults. Plasma cortisol in week of life. Cortisol levels in preterm infants are higher than well term infants (but similar to sick term babies). Cortisol rises after birth to r falling further thereafter. Cortisol is released in a pulsatile manner, with a five secretory bursts 6h, and the cortisol production rate is around d 8mg m2 day in term infants, and 21 11 mg m2 day in preterm infants. Diurnal variation in cortisol develops at 8-12 weeks in term infants. Preterm infants 31-week gestation develop diurnal variation at a similar postnatal when in the home environment, but hospitalized infants below this gestation do not. Although cortisol production rates in preterm infants are not low, some differences in HPA response to stimulation have been associated with differences in clinical course. This has raised the hypothesis that preterm infants may not produce...

GH Receptor Belongs to the Cytokine Receptor Superfamily

Three pairs of conserved cysteine residues, which form intrachain disulfide linkages, a fibronectin-like domain, and a WSXWS-like motif, which in mammalian GHRs has the sequence YXXFS, where X represents a nonconserved amino acid (Fig. 4). Within the superfamily, GHR belongs to the type I cytokine receptor family, which includes the closely related prolactin receptor as well as receptors for various interleukins and colony-stimulating factors, erythro-poietin, thrombopoietin, and leptin. The conserved cysteine residues and the WSXWS-like sequence of GHR help form and or support the receptor's extracellular ligand binding pockets. Although GHR's WSXWS-like motif does not contact GH directly, it is essential for ligand binding and signal transduction, as demonstrated by alanine-scanning mutagenesis, and as indicated by the GH resistance phenotype seen in sex-linked dwarf chickens, where the motif's terminal serine is mutated to isoleucine. In addition, GHR and the other cytokine...

Steroid Ligand Selectivity

Steroid hormones such as cortisol, corticosterone, testosterone, progesterone and estrogen share a similar core chemical structure but mediate distinct biological responses. Structural comparisons of GR, AR, PR, and ER have now provided some insight into how specificity is achieved by the steroid receptors. In the structures of steroid receptors complexed with steroid agonists, the core steroid template assumes a common orientation with the A-ring oriented toward a conserved argi-nine from helix-5 and the D-ring toward helix-12. However, many subtle differences in the secondary structure and the topology of the ligand-binding pockets exist in different steroid receptors. In particular, helices-6 and -7 of GR deviate significantly from ER, AR and PR and produce a unique side pocket in GR. This pocket may account for the GR selectivity of glucocorticoids, which have larger substituents at the C17a position compared with estrogen, progesterone and testosterone. Interestingly, the...

Spontaneously Arising Phenotypic Models

Mutations which cause disease can arise spontaneously. Genetic mapping methods utilizing positional cloning can help identify disease-causative genes and their proteins in animals which have spontaneously developed diseases similar to those of humans. An example of this type of technology is the ob ob genetic mouse, which is obese, and has mutations in a gene for a peptide hormone known as leptin. This mouse, and its counterpart the db db mouse, which has mutations in the leptin receptor, can be used as animal models for obesity. A similar mouse, the Agouti strain, is also obese and has defects in melanocortin receptors, which regulate hair color as well as appetite, and the expression or release of leptin by adipose tissue. The Agouti mouse develops type II diabetes, and therefore can be used as an animal model of that disease in humans. Of course, human disease is rarely as simple as a single genetic misread, so these models must be used with some caution when testing drugs or when...

Antley Bixler syndrome

Features include craniosynostosis resulting in trapezoidocephaly, midface hypoplasia, proptosis, choanal stenosis or atresia, humeroradial synostosis, bowing of the femora and ulnas, long bone fractures, long slender fingers with camptodactyly, and cardiac and renal malformations. The Antley-Bixler syndrome can be caused by mutations in fibroblast growth factor receptor 2 gene (FGFR2). About 50 of reported cases have been associated with ambiguous genitalia and adrenal dysfunction, but it is now thought that these may represent a distinct disorder caused by mutations in the cytochrome P450 oxidoreductase (POR) gene. In POR deficiency females may be virilized, and males undervirilized, and cortisol synthesis is impaired.

Four aHelix Bundle Cytokines

Comparison of the tertiary structure of long-chain four a-helix bundle cytokines GH (de Vos, 1992), IL-6 (Somers, 1997), LIF (Smith DK, 1998), leptin (Zhang, 1997). Fig. 1. Comparison of the tertiary structure of long-chain four a-helix bundle cytokines GH (de Vos, 1992), IL-6 (Somers, 1997), LIF (Smith DK, 1998), leptin (Zhang, 1997). in up-up-down-down topology (Bazan, 1991 Sprang and Bazan, 1993 Walter, 1997). Thus far, crystal structures have been determined for the short-chain four a-helix bundle cytokines IL-2, IL-4, IL-3, IL-5, GM-CSF, and M-CSF, as well as the long-chain four a-helix bundle cytokines IL-6, LIF, CNTF, GH, G-CSF, and leptin (Somers et al., 1997 Zhang et al., 1997, for review see Simpson et al., 1997). Several other cytokines are predicted to fold in a similar way (Fig. 1).

Cutaneous viral infections

Research into the relationship between life stress and human papillomavirus (HPV) and human immunodeficiency virus (HIV) suggests that major psychosocial events are implicated in immune decrements in HPV infections and tendency to intraepithelial neoplasia (Pereira et al., 2003). Further studies on the stress management effects on psychological, endocrinological and immune functioning in men with HIV infection suggested that psychotherapy had measureable beneficial effects. A 10-week, group-based cognitive-behavioural stress-management intervention showed reductions in catecholamine urine output, urine cortisol output and beneficial changes in CD8 cytotoxic and CD4 lymphocytes (Hickie et al., 1999).

Examples of Induction of Pathology as a Tool to Study Aging

Premature aging has been induced in a number of laboratory animals as well as in captive wild animals by various methods. One of the favorite methods is to expose the animal to stress, that is, to excessive environmental (including physical, emotional, and social) demands. Stress will activate or interfere with all major regulatory systems, that is, it will disturb neuroendocrine balance (Chapter 9), alter immunologic competence (Chapter 14), and increase the production of free radicals (93). Stress or injection of cortisol to mimic adrenocortical stimulation, in

What to tell parents

A brief explanation of the effects of steroids (maintaining blood glucose, blood pressure, and response to stress), and therefore the problems of adrenal deficiency. Initially it may be difficult to ascertain whether there is a problem with the adrenal gland, but it is important to perform tests (blood cortisol, urine steroid profile, and Synacthen test) that will show how the gland is working. In the interim it may be necessary to give steroid therapy until the results are known.

The fetal adrenal gland

D the enzymes for Cortisol production (functionally identical to FZ in early with the substrate for oestrogen synthesis. The fetal adrenal cortex produces DHEAS and cortisol from early gestation (6-12 weeks), but controversy exists as to whether cortisol is produced de novo or derived from the metabolism of progesterone. The fetus appears to be protected from high levels of cortisol in utero, as cortisol is converted to biologically inactive cortisone by the enzyme 11P-HSD2 in placental and fetal tissues. Eighty per cent of maternal cortisol is inactivated in its passage across the placenta. Synthetic gluco-corticoids, such as dexamethasone, are a poor substrate for this enzyme and so reach the fetus to exert pharmacological effects. The fetal adrenal gland is probably under the control of ACTH from the fetal pituitary, but the placenta also produces ACTH and corticotrophin-releasing hormone (CRH). In other species the adrenal gland is involved in the initiation of parturition with a...

Reninangiotensin system

The renin-angiotensin system is the main regulator of aldosterone secretion. Renin is a proteolytic enzyme secreted by juxtaglomerular cells surrounding the afferent arteriole in the kidney, adjacent to the macula densa. Renin is released in response to a fall in plasma volume. Renin converts angiotensinogen (from the liver) to angiotensin I, which is subsequently converted to Angiotensin II (a potent pressor) by angiotensin converting enzyme (ACE) primarily in the lung. Angiotensin II acts directly on the zona glomerulosa cells in the adrenal cortex to produce aldosterone. Aldosterone acts on the distal tubule and collecting ducts of the kidney to increase sodium reabsorption and excretion of potassium and hydrogen. Both cortisol and aldosterone can act on the mineralocorticoid receptor (MR), but there is local enzyme inactivation of cortisol in the kidney to prevent cortisol acting on the MR at this site (deficiency in this enzyme causes further ADH secretion. ADH acts on...

Physiology of Intake Regulation

Food intake is regulated in the central nervous system, which receives input from sensory properties of food, mechanical and chemical receptors in the gut, circulating metabolites, and hormones. A complex neuronal circuitry involving the hypothalamus, brainstem and cortex integrates these signals and translates them into information regulating meal size and duration, interval to the next meal, the amount of food consumed over the day or several days, weeks and months, and possibly the composition of food as well as the intake of total energy (fig. 1). The hypothalamus regulates both long-term and short-term intake. The long-term regulation of food intake is mediated by leptin and insulin secreted in proportion to the adipose tissue mass and exerting their action in the hypothalamus 4, 5 . These hormones affect the amount of food Long-term regulation Adipose tissue, insulin, leptin

Short Term Intake Regulation

The secretion of hormones controlling food intake is regulated by the presence of food in the GI tract. The gut is a source of numerous peptides that contribute to the regulation of intake and metabolism. These include, from the small intestine, cholecystokinin (CCK), glucagon-like peptides (GLPs) 1 and 2, bombesin, gastrin-releasing peptide, neuromedin B, glucagon, apolipoprotein A-IV, amylin, somatostatin, enterostatin and peptide YY (3-36) and from the stomach, ghrelin and leptin 7, 11 . Many of the GI hormones and or their receptors are also expressed in the central nervous system, underlining their important role in appetite control 11 . Some enter the central circulation via leaky areas (brainstem and hindbrain) in the blood-brain barrier, or send signals through vagal afferents that are relayed to the hypothalamus. The macronutri-ent-dependent release of gut hormones might explain, at least in part, differences in the satiating and satiety effect of macronutrients. For example,...

HPA Axis Alterations in Other Psychiatric Disorders

When depression is comorbid with a variety of other disorders, such as multiple sclerosis, Alzheimer's disease, multi-infarct dementia, Hunting-ton's disease, and others, both CRF hypersecretion and HPA axis hyper-activity are common. In contrast, HPA axis dysfunction has rarely been reported in schizophrenia. Consistent with the role of CRF in both depression-like and anxiety-like behaviours in preclinical animal studies, increased CSF concentrations of CRF have been reported in post-traumatic stress disorder (PTSD) 95 . A recent elegant study that used an in-dwelling cannula in the lumbar space, allowing repeated sampling of CSF several hours after the initial, and presumably stressful, lumbar puncture, demonstrated elevated CSF levels of CRF in combat veterans suffering from PTSD 96 . In contrast, low serum cortisol and urinary free cortisol levels have been repeatedly, yet unexpectedly, detected in PTSD. One possible mechanism that has been proposed by Yehuda et al. 97 suggests...

Hepatic Drug Metabolizing Changes

The clearances of drugs metabolized by CYP3A4 have been shown to be consistently increased in multiple studies of pregnant women. Because midazo-lam is exclusively eliminated by CYP3A4 metabolism (34, 35), midazolam clearance and the serum concentration ratio of 1'-hydroxymidazolam to midazolam are recognized markers of CYP3A4 activity. (36, 37) In pregnant women at term, the clearance of mida-zolam has been shown to be 2.9-fold greater than in nonpregnant women (38). The metabolic ratio of cortisol, a nonspecific probe of CYP3A4 activity, was increased in pregnant women near term when compared to the same women 1 week and 3 months postpartum (39). The clearance of nifedipine was increased 4-fold in women during the third trimester of pregnancy in comparison to historical controls (40). Methadone, a drug used to treat heroin addiction during pregnancy, also is a CYP3A4 substrate. In a study of methadone pharmacokinetics during pregnancy, methadone clearance doubled in the midtrimester...

Improving Crystal Packing by Point Mutation

Wild type human leptin aggregates extensively. A single mutation of Trp-to-Glu at residue 100 on the surface of the molecule dramatically improved the solubility, allowed crystallization and provided structural information to 2.4 A resolution 26 . The tryptophan residue was not conserved in the sequence alignment of leptin from ten different species. Mutagenesis studies on the 24 kDa fragment of the DNA gyrase B subunit from E. coli further confirmed that single amino acid changes on the surface can dramatically change crystallization properties 27 . Three out of nine mutants produced crystals with different morphology to that of the wild type protein. The F104Y mutant diffracted to 2.44 A resolution, an improvement over the 2.9 A resolution obtained from the crystals of the wild type protein.

Directed fetal placental signals and fetal placental maternal interactions

Determination of the fetal signal could have therapeutic implications for pre-eclampsia and IUGR. What are the possible candidates The placenta produces a number of molecules that might potentially modify maternal physiology and metabolism and placental function. These include norepinephrine (Manyonda et al., 1998 Sarkar et a ., 2001 Sodha et a ., 1984), acetylcholine (Sastry, 1997), CRH (Fadalti et a ., 2000 Karteris et a ., 2001, 2003) and leptin (Ashworth et a ., 2000 Domali and Messinis, 2002 Mantzoros, 2000 Poston, 2002 Sagawa et a ., 2002) to name a few. We believe that of the placental hormones listed, leptin holds special promise as one of the putative signals to modify maternal and placental function to augment nutrient delivery. Leptin has numerous effects to alter energy metabolism and influence adiposity (Harris, 2000). Many of these are quite relevant to the metabolic adaptations of pregnancy that are accentuated in pre-eclampsia. Leptin acts centrally to increase...

Mechanisms of altered lipid metabolism in preeclampsia

It is likely that both maternal and placental factors cause dyslipidemia in pre-eclampsia. The insulin resistance syndrome, a cluster of metabolic abnormalities associated with reduced insulin sensitivity, is a strong predisposing factor for cardiovascular disease (Kahn and Flier, 2000 Reaven, 1994). Pre-eclampsia is associated with accentuation of many features of the metabolic syndrome, including insulin resistance, hypertri-glyceridemia, elevated FFA, low HDL cholesterol, hyperuricemia, and abnormalities in the fibrinoly-tic system, usually in the absence of frank diabetes (Kaaja, 1998 Kaaja et al., 1995 Lorentzen et al., 1998 Solomon et al., 1994 Solomon et al., 1999 Sowers et al., 1995 Wolf et al., 2002). Accompanying abnormalities include increased serum concentrations of leptin, C-reactive protein, tumor necrosis factor-a, testosterone, and plasminogen activator-inhibitor-1 (Sattar and Greer, 2002 Wolf etal., 2001).

PDEs Are Integrators of Different Signaling Pathways

Lipolysis Anp

Cal observations, as well as experiments with reconstitution systems, this kinase is most likely the recently discovered PKB-AKT. Finally, leptin, a recently discovered hormone that controls food intake, also signals through the PI3 kinases-PDE3 pathway. In P cells of the pancreas, leptin causes the activation of PDE3B, which leads to a marked inhibition of insulin secretion stimulated by the glucagon-like peptide-1.

Reproductive Endocrinology Diagnostic Imaging

Normal Follicular Ultrasound Chart

An abdominal ultrasound can provide immediate data to assist a family in understanding their newborn's phenotype, likely gender assignment and reproductive potential. An abdominal ultrasound should be immediately performed to assess the presence of a cervix, uterus, fallopian tubes, and ovaries or gonads. Evidence of a uterus on ultrasound is the most important finding and will most likely reassure parents that their newborn will develop into a phenotypic female. The most common cause of virilization of a female infant at birth is congenital adrenal hyperpla-sia, which can be managed medically by replacing cortisol.

Posttraumatic Stress Disorder and Neurochemical Processes

Notes The amygdala is activated, which activates the hypothalamus, which releases CRF (or CRH). The anterior pituitary releases adrenocorticotropic hormone (ACTH). The adrenal cortex releases glucocorticoids (e.g., cortisol), which effect glucose metabolism by helping break down proteins and converting them to glucose, making fat available for energy, increasing blood flow, and stimulating responsive behavior. The sympathetic nervous system activates the adrenal medulla, which releases norepinephrine and epinephrine. Epinephrine activates glucose metabolism, which provides the brain and body energy to respond to the threat and serves to increase blood flow to muscles by increasing heart output. Norepinephrine is both a stress hormone and a neurotransmitter and is involved in the stimulation of heart activity, dilation of blood vessels, and increase in respiration. Hormones and peptides (glucocorticoids (e.g., cortisol) and corticotropin-releasing factor) In turn, the amygdala...

Principles of Teratology

The principles of teratology have been articulated by Wilson (104). The first principle is that terato-gens act with specificity. A teratogen produces a specific abnormality or constellation of abnormalities. For example, thalidomide produces phocomelia, and valproic acid produces neural tube defects. This specificity also applies to species, because drug effects may be seen in one species and not in another. The best example is cortisol, which produces cleft palate in mice but not in humans.

Structure Of The Skin

The subcutaneous fat layer acts both as an insulator, a shock absorber, reserve depot of calories and supplier of nutrients to the other two layers. This subcutaneous tissue or hypodermis is composed of loose, fibrous connective tissue which contains fat and elastic fibres. The base of the hair follicles are present in this layer, as are the secretory portion of the sweat glands, cutaneous nerves and blood and lymph networks. It is generally considered that the drug has entered the systemic circulation if it reaches this layer however the fat deposits may serve as a deep compartment for the drug and this can delay entry into the blood.

General Adaptation Syndrome

The first stage begins when an individual becomes frightened, anxious, or even merely concerned. The body immediately undergoes numerous physical changes to cope with the stressor. Metabolism speeds up. Heart and respiration rates increase. The hormones epinephrine, norepinephrine, and cortisol are secreted. Sugar is released from the liver. The muscles tense. Blood shifts from the internal organs to the skeletal musculature. These and a host of other changes are aimed at helping the body cope, but the price paid for this heightened state of arousal typically includes symptoms such as headache, upset stomach, sleeplessness, fatigue, diarrhea, and loss of appetite. The body's increase in alertness and energy is accompanied by a lowered state of resistance to illness.

Protein Orientation and Subsequent Activity Optimised Antibody Immobilisation Protocol

The immobilisation of a mouse IgG3 antibody raised to Cortisol (anticortisol) is summarised in Table 3. The experimental protocol was as follows. A thiol functionalised chip was first calibrated using standard calibrant solutions and then subjected to ester (sulpho-GMBS), which is a thiol amine linker followed by protein G. Once the protein G had been immobilised (via the sulpho-GMBS linker) the surface was ready for the immobilisation of the IgG3 antibody itself. Protein G has the capability to orient the antibody by interacting specifically with the Fc region, ensuring that the antibody remains active once immobilised. As can be seen from Table 3, the layer thickness increases by over 15 nm on the addition of the antibody. This is entirely consistent with the long axis of the IgG3 antibody (typically 12-15 nm, the other two axes typically being of the order of 5-10 nm) being immobilised normal to the sensor surface. This is shown schematically in Fig. 5. 3 IgG3 anti-cortisol 15.126...

Mechanisms Of Parturition Parturition

Signals for myometrial activation also come from the fetal HPA axis (Liggins and Thor-burn, 1994). It is currently thought that once fetal maturity has been reached (as determined by as yet unknown mechanisms), the fetal hypothalamus and or the placenta (see below) increase the level of CRH secretion, which in turn stimulates adrenocorticotropic hormone (ACTH) expression by the fetal pituitary and cortisol and androgen production by the fetal adrenals. Fetal an-drogens are then aromatized into estrogens by the placenta. Ultimately, this initiates a biological cascade that leads to a common pathway of parturition characterized by uterine contractility, cervical ripening and decidual fetal membrane activation seen in Phase 2 of parturition. Placental CRH synthesis is stimulated by glucocorticoids, in contrast to the inhibitory effect of glucocorticoids on hypothalamic CRH synthesis. Placental CRH, in turn, promotes fetal cortisol and DHEA-S production, and this positive-feedback loop is...

AT1 receptor autoantibodies

Martinez-Abundis, E., Gonzalez-Ortiz, M. and Pascoe-Gonzalez, S. (2000). Serum leptin levels and the severity of preeclampsia. Arch. Gynecol. Obstet., 264, 71-3. Masuzaki, H., Ogawa, Y., Sagawa, N., et al. (1997). Nonadipose tissue production of leptin leptin as a novel placenta-derived hormone in humans. Nat. Med., 3, 1029-33.

Infection and Inflammation

Another complementary mechanism by which intrauterine infection leads to preterm birth is by activation of the fetal HPA axis. Increases in fetal cortisol and fetal adrenal androgen levels have been reported among the fetuses of women with intrauterine infections (Gravett et al., 2000 Yoon et al., 1998) and in nonhuman primates with experimental intra-amniotic infections (Gravett et al., 1996).

Nervous System Endocrine System Interactions

If the pituitary gland releases adrenocorticotropic hormone (ACTH), the adrenal glands will be activated to release their hormones. The adrenal cortex produces and secretes a variety of hormones, such as aldosterone, which regulates the blood-salt balance directly and blood pressure indirectly cortisol, which accelerates body metabolism and androgens, or sex hormones. All of these are steroid hormones, which are involved in rapidly preparing the body for strenuous performance. Even more pronounced are the effects of the adrenal medulla, which produces and secretes the hormone neurotransmitters epinephrine and norepinephrine these two hormones accelerate heart, muscle, and nerve action as well as stimulate the release of fat and sugar into the bloodstream for quick energy, all of which are extremely important for spontaneous activity such as fighting with or fleeing from enemies. The control of sugar storage and release from the liver by the pancreatic hormones insulin and glucagon...

Metabolism and the systemic inflammatory response

The syndrome results from the fact that adipose tissue is not merely an energy store but a source of pro-inflammatory cytokines and other metabolic mediators. It is a major source of TNF-a, inter-leukin-6 (IL-6), leptin, a hormone that regulates appetite and energy expenditure, and plasminogen activator-1 (PAI-1). Thus there is a significant correlation between body mass index, circulating leptin and TNF-a and IL-6 in humans (Mantzoros et al., 1997). Leptin has pro-inflammatory actions as does TNF-a (Zarkesh-Esfahani et al., 2001). The net effect is that obesity is a state of chronic systemic inflammation. IL-6 induces the acute phase response, of which circulating C-reactive protein (CRP) is the classical example (Bastard et al., 2000 Yudkin et al., 1999). The importance of obesity in generating the inflammatory response is demonstrated by its reversal after weight loss (Ziccardi et al., 2002).

Other Forms of Stress Exposure

Maternal stress can cause the release of increased levels of catecholamines and cortisol, which could prematurely activate placental corticotropin-releasing hormone, thereby precipitating the biological cascade leading to the onset of preterm labor (see Chapter 6). Stress can also alter immune function, leading to increased susceptibility to intra-amniotic infection or inflammation (Wadhwa et al., 2001). Additionally, stress may induce high-risk behaviors as a means of coping with stress (Whitehead et al., 2003).

Measurement of peptide hormones as markers of placental function

The ischemic hypoxic injury suffered by tropho-blast in pre-eclampsia may alter its functional activity manifest as changes in production of peptide or steroid hormones and help predict the disease. While there are potential circulating markers of trophoblast invasion that can be measured as yet none have been correlated with invasion hence hormone measurements in maternal plasma more likely reflect villous trophoblast function. Concentrations of corticotro-phin-releasing hormone (CRH) synthesized by trophoblast increase exponentially throughout gestation, but the effect of CRH is negated by a 34kda CRH binding protein in maternal plasma. CRH concentrations are increased in individuals with pre-eclampsia and are accompanied by a decrease in CRH binding protein (CRHbp) (Perkins et al., 1995). Interestingly, trophoblast production of CRH, unlike maternal CRH, can be stimulated by cortisol, the increase in CRH in pre-eclampsia may be due to increased fetal cortisol, itself a reflection...

HPA Axis Abnormalities in Depression

The earliest studies in this field demonstrated elevated plasma cortisol concentrations in depressed patients 40,41 . Other markers of hypercortisolism that have been reliably demonstrated in depressed patients include elevated 24-hour urinary free cortisol concentrations and increased levels of cortisol metabolites in urine 42 . One commonly used test to measure HPA axis function is the dexamethasone suppression test (DST). In this test, lmg dexamethasone is given at ll p.m., blood is then drawn at 8 a.m. the following morning and cortisol levels measured. Dexamethasone is a synthetic steroid similar to cortisol and suppresses ACTH secretion, and subsequently cortisol release, in healthy volunteers. Non-suppression of plasma glucocorticoid levels following the administration of dexamethasone is common in depression. The rate of cortisol non-suppression after dexa-methasone administration generally correlates with the severity of depression 43 in fact, nearly all patients with major...

Animal Models of Preterm Birth

Spontaneous preterm birth occurs infrequently in most species. This has limited research in this area to specific pharmacological or environmental interventions that result in preterm birth. Pharmacological administration of RU-486, a progesterone antagonist, leads to preterm delivery in rodents but not in nonhuman primates (Dudley et al., 1996 Garfield et al., 1987 Ha-luska et al., 1994). Administration of cortisol (Grigsby et al., 2000) or maternal starvation (protein and caloric restriction) (Kumarasamy et al., 2005) leads to preterm delivery in sheep.

Animal Models For Preterm Birth And Neonatal Sequelae

Although most animal species do not have significant rates of spontaneous preterm birth, there is much interest in the use of relevant animal models to elucidate the mechanisms of preterm birth and the neonatal sequelae of prematurity and to develop rationale and efficacious treatment and prevention strategies. However, in choosing an appropriate animal model, a necessary caveat is that many species differ from humans in the length of gestation and the number of fetuses, the type of placentation, the hormonal control of parturition, and the timing of fetal organ maturation (Table 6-2 and Figure 6-3). For example, lower mammalian species such as rats, rabbits, and mice have short gestational periods with multiple fetuses and delayed maturation of the fetal brain. Sheep, another commonly used experimental model, have a longer gestation and a singleton pregnancy, similar to humans, but have different placentation and parturition is initiated by abrupt increases in cortisol levels, which...

Major depressive disorder

The vegetative disturbances associated with depressive disease are a central feature of the syndrome (American Psychiatric Association, 1994). It is well recognised that depressive disorder is accompanied by measurable alterations of circadian rhythms for example, cortisol secretion and the sleep-wake cycle. A commonly encountered clinical feature of circadian rhythm disturbance is the worsening of mood, energy and psychomotor activity early in the day with an improvement during the latter part of the day. Another disturbance of biological rhythm encountered in mood disorders is seasonal worsening of depressive symptoms in some patients, especially during the fall and winter months. The depression-related somatic concerns related to the integumentary system, or symptoms which are related to depression such as pruritus can therefore also manifest a diurnal or seasonal pattern.

Ultrasonically Enhanced Drug Delivery 13231 Sonophoresis

Sonophoresis, or phonophoresis as it is sometimes called, is the term used to describe the ultrasonically induced increase in penetration of pharmocologically active agents through the skin or through other anatomical barriers or membranes (Skauen & Zenter 1984). The possible mechanisms responsible for sonophoresis are heating, cavitation and microstreaming. It seems improbable that heating is responsible because similar effects are not achieved by other heating techniques (Meidan et al. 1995). Bommannan et al. (1992a, b) have suggested that cavitation may be involved, although this seems unlikely at the exposure levels generally used. The 'stirring' produced by acoustic streaming may perturb any barriers to perfusion at the skin, thus allowing enhanced perfusion (Ziskin & Michlovitch 1986). Griffin and Touchstone (1963, 1972) and Griffin et al. (1965) showed an increase in cortisol level intramuscularly and within the paravertebral nerve as a result of ultrasound exposure. As a...

Impairment Of Ltp In Response To Stress

Stress can be defined as a threatening and inescapable situation or event that can promote physiological and behavioral disturbances ranging from psychiatric (particularly mood) disorders to immunological dysfunctions. Specifically, the dramatic increase in corticosteroid hormones (mainly corticosterone in rodents, cortisol in human) is defined as a physiological marker of stress (Kim and Diamond, 2002). Until recently, the impact of stress has been mostly studied on the hippocampus, a key target of stress hormones. Exposure to stress affects structural and synaptic plasticity in the hippocampus, and the increased expression of glucocorticoid receptors in this structure has been linked to learning and memory deficits (Magarinos et al., 1996 Garcia, 2001). In addition to the hippocampus, the PFC is also a region that can be up-regulated by environmental stimulation, and its role in stress, particularly its medial part, is well documented. A number of studies have reported the...

History

Initial studies of immune function in psychiatric patients had shown reduced lymphocyte numbers and diurnal variability in psychosis (Freeman & Elmadjian, 1947), and poorer antibody response to pertussis vaccination in schizophrenia. Further changes were shown in cellular immunocompetency and urinary stress cortisol levels in psychiatric patients (Kiecolt Glaser et al., 1984).

Stress

Although intervention trials on stress per se and preterm birth are absent or their findings are inconclusive, a handful of more rigorous observational studies on stressors (environmental demands) and preterm birth now exist. A second group of acceptable studies that have evaluated emotional, affective, or cognitive stress-related states and preterm birth exist. In addition, a number of notable animal and human studies on specific linkages between stress or emotion and various hypothesized mediators of preterm birth have been published. These mediators include BV (Culhane et al., 2001), cytokines (Coussons-Read et al., 2005), corticotropin-releasing hormone (Hobel et al., 1998 Lockwood, 1999 Mancuso et al., 2004), cortisol (Obel et al., 2005), blood pressure (McCubbin et al., 1996 Stancil et al., 2000), uterine artery resistance (Teixeira et al., 1999), and pregnancy-induced hypertension (Landsbergis and Hatch, 1996). This literature is discussed elsewhere in this report (Chapter 6)....

Tissue Remodelling

As mentioned, stress has been shown to lead over time to cell death in the hippocampus. Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls 64 . Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels in the studied population. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.

The Amygdalas

In response to anxiogenic stimuli, the central nucleus of the amygdala solicits, either directly or indirectly through the BNST, the hypothalamic paraventricular nucleus (PVN) and the locus coeruleus. This latter is essential for the production of noradrenaline, which raises blood pressure, accelerates heart rate, and-with the nucleus accumbens-activates a motor reaction the PVN then produces corticotropin-releasing factor (CRF), which stimulates the pituitary (PIT) to release adrenocorticotrop-ic hormone (ACTH), which is carried in the bloodstream to the adrenals. Cortisol, a hormone secreted by the capsules, then returns to the brain in the bloodstream, regulating pituitary stimulation. The body thus finds the sympathetic system activated and can prepare itself-or at least predispose itself-to attack or to flee. Cortisol activates the hippocampus to record explicit memories that are particularly significant for survival, but when there is too much stimulation, or for too long a...

Stage

Thus, increased insulin resistance, LDL cholesterol, triglycerides, uric acid, and reduced HDL cholesterol are all present in pre-eclampsia. These have suggested a similarity between pre-eclampsia and later-life atherosclerosis (Roberts and Lain, 2002). Leptin and sympathetic output that increase fat mobilization are also increased in women with preeclampsia. As with the physiological changes, many of these differences can be demonstrated in very early pregnancy and can be detected years postpartum (Hubel etal., 1998 Laivuori etal., 1996, 1998, 2000 Lorentzen etal., 1994). Several of these alterations could be secondary to increased activation of the inflammatory response. Interestingly, these metabolic modifications all increase potential nutrient availability for the fetus.

Rarer causes of CAH

Over 90 of cases of CAH are due to 21-OHD, which can be identified most quickly by raised plasma 17a-OHP Infants with this condition usually make sufficient cortisol for needs unless stressed, and this should allow time to collect diagnostic samples before starting steroid treatment.

Signal

Figure 4.4 Overview of the feedback mechanisms of the hypothalamic-pituitary-adrenal axis. Following relevant stimuli, including stress, corticotropin-releasing factor (CRF) is released from the hypothalamus into hypophyseal portal vessels, where it is transported in high concentrations to the pituitary gland. CRF then promotes the release of adrenocorticotropin (ACTH), which in turn promotes the release of cortisol from the adrenal glands. Cortisol acts as an inhibitory signal at both the hypothalamus and pituitary, preventing further CRF and ACTH release, respectively. Mounting evidence suggests that chronic overactivity of the axis, and particularly overproduction of CRF, may contribute to the pathophysiology of depression. Reproduced from 82 with permission release of its post-translational products ACTH, -endorphin and others (Figure 4.4). AVP can also promote the release of ACTH from the anterior pituitary, though CRF is necessary for AVP to exert this effect. ACTH released from...

Genetic Factors

Risk increases associated with shorter TA repeats and the T allele of the A49T marker, but not for other studied markers.96 Markers in several other genes, including cytochrome p450-17 (CYP17), cytochrome p450-19 aromatase (CYP19), cytochrome p450-1A1 (CYP1A1) and cytochrome p450-3A4 (CYP3A4) have shown promising initial results that often cannot be replicated.110'111'119'120'125'134-148 Furthermore, recent initial studies of 17P-hydroxysteroid dehydrogenase 3 (HSD17B3) and 3 P-hydroxysteroid dehydrogenase 1 (HSD3B1) have shown promising results,149'150 but further study is needed to elucidate the role these may play in prostate cancer.

Interpretation

It is usual to measure both ACTH and cortisol in response to hCRH, but this poses practical difficulties. ACTH has an extremely short half-life and so requires special handling (usually collected on ice), and the assay may not be available in all laboratories. Measurement of cortisol alone in response to hCRH gives an indirect measure of pituitary and adrenal function, as it depends on the integrity of both glands. a cortisol level above 360 nmol L at 60 min or a cortisol rise of 150-200 nmol L at 30 min. Side effects - dramatic flushing.

White Fat Depots

The initial characterization of SSAT-overexpressing mice revealed, in addition to hairlessness, practically a total lack of subcutaneous fat depots (7). Subsequently, we found that these animals also lacked visceral fat depots and thus were severely lipo-atrophic. In contrast to other lipoatrophic mouse models, SSAT transgenics did not show any triglyceride accumulation in nonadipose tissues and they fully retained insulin sensitivity (21). On fasting, the transgenic animals showed severely impaired ketogenesis, very low plasma leptin level, and significantly reduced triglyceride, glucose, and insulin levels. The transgenic animals also exhibited significantly elevated basal metabolic rate in comparison with the wild-type animals, indicating a greater expenditure of energy (21). It thus appears that generalized SSAT overexpression causes lipoatrophy, but also

Specific Hormones

Kallmann Syndrome Penis

REGULATED BY Corticotropin releasing hormone (CRH) from hypothalamus, which in turn is regulated by negative feedback from blood levels of Cortisol to both the hypothalamus (decreasing CRH secretion) and anterior pituitary gland (decreasing ACTH secretion). In addition, stress itself, whether physical or mental, can trigger CRH release through neural communication to the hypothalamus. FUNCTION Stimulates secretion of Cortisol (a glucocorticoid) and also, to some degree, aldosterone (a mineralocorticoid) and androgenic steroids in the adrenal cortex. DEFICIENCY Although pituitary disease may be a cause of adrenal cortical deficiency (Addison's disease), most cases result from destruction of the adrenal cortex. Lack of aldosterone results in fluid loss that may cause hypotension, even shock and death, hyponatremia (decreased plasma sodium), hyperkalemia (high plasma potassium), and acidosis from inability of sodium to be reabsorbed in the kidney in exchange for H + . Loss of Cortisol...

Pain and Discomfort

The relationships between frequent or chronic pain, the stress response, cortisol levels, and the neurodevelopment of the preterm infant are extremely complex (Grunau, 2002 Clin Perinatol 29 373 Grunau et al., 2006 Seminars in Perinatology in press). The fetus or preterm infant responds to painful stimuli with increases in cortisol and endorphin levels as early as 23 weeks of gestation, but the neurotransmitters that attenuate pain develop later in postnatal life (Anand, 1998 Biol Neonate 73 1 Fitzgerald et al., 1988 Lancet 1 292 Fitzgerald et al., 1999 Pain 39 31 Franck et al., 2000 Pediatr Clin North Am 47 487).

Implantation Errors

A direct causal link between implantation problems and spontaneous preterm delivery has not been established in animal or human studies nonetheless, indirect evidence suggests that this may be an important area for further research. The nonpregnant endometrial cavity is frequently colonized by microorganisms (Arechavaleta-Velasco et al., 2002 Romero et al., 2004b), and subclinical endometrial infection or inflammation may impair implantation or placentation, possibly by eliciting an antitrophoblast immune response that results in apoptosis, reduced tro-phoblast invasion and remodeling of the deciduas and uterine arterial vessels, and the arrest of early embryonic development (Romero et al., 2004b). This raises the possibility that inflammation in the endometrium around the time of implantation may contribute to subsequent preterm delivery. Furthermore, a normal pregnancy is characterized by a shift from a proinflammatory Th1-type response toward an anti-inflammatory Th2-type response...

Selective Longevity

Rapid senescence is usually observed in organisms that have a short period of optimal function in adult life. In addition to the ones listed in Figure 1, the Pacific salmon (Oncorhynkus) represents a prime example of an organism characteristic of this group. The salmon undergoes severe stress (with high blood cortisol levels, Chapter 9) at the time of spawning and dies shortly thereafter at about one year of age (6). However, if reproduction and the associated stress are blocked, the salmon will continue to live for some (six to seven) years (6). Other species fitting into this category, and listed in Figure 1, include yeast, some nematodes (Caenorhabditis), the housefly (Drosophila), and some longer-lived (10-100 years) species that

Control Mechanisms

Altered expression of genes regulating insulin has been offered as an explanation of the development of obesity through loss of intake control early in life. Insulin is intimately involved in both long- and short-term intake control and the actions of both insulin and leptin are modified by malnutrition. Programmed development of obesity and adipogenic diabetes in rats has been attributed to a permanent dysregulation of the adipoinsular feedback system, again amplified by a hypercaloric diet, leading to hyperleptinemia, leptin resistance, hyperinsulinemia, and compensatory leptin production by pancreatic 8 cells 33 . The offspring of undernourished mothers (30 of the ad libitum intake of the control mothers), cross-fostered during lactation to the control mothers, had lower birth weights than the offspring of control mothers 34 . After weaning, they exhibited higher food intake, systolic blood pressure, and fasting plasma insulin and leptin concentrations than control pups. These...

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