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Role of Leptin in Inflammation and Its Possible Connection to Obesity in Schizophrenia

However, the adipocytes and macrophages are responsible for the increase not only of the pro-inflammatory cytokines but also for leptin and resistin. The increase in leptin exerts a strong negative feedback on insulin sensitivity thereby enhancing insulin resistance 43 . This situation is compounded by the impact of the glucocorticoids on the regulation of leptin hypercortisolemia, a common feature of schizophrenia and other major psychiatric disorders, stimulates the release of leptin and thereby further enhances insulin resistance 44 . Irrespective of the cause, epidemiological evidence suggests that obesity increases the risk of autoimmune disease and such immune related diseases as asthma. It has been speculated that this arises due to the decrease in immunological tolerance associated with the increase in the pro-inflammatory cytokines and leptin, and the decrease in adiponectin 47 . It has been demonstrated that both IL-6 and leptin downregulate the regulatory T...

Central and Physical Effects of Hypercortisolaemia

A well-established effect of high levels of cortisol is hippocampal shrinkage 35 . Compared to healthy controls both first-episode and patients with chronic schizophrenia have reduced hippocampal volumes as demonstrated by imaging and neuro-pathological studies 36, 37 . Such structural changes are associated with functional deficits in memory (verbal) and executive function 38 . The exact etiology of hippocampal volume reduction remains unclear but is attributed to both genetic and environmental factors such as, prenatal exposure to maternal stress, iatrogenic gluco-corticoid administration, illicit drug usage and alcohol abuse and perinatal complications 39, 40 . Yet GCs also have peripheral effects as manifested by Cushing's disease (due to a pituitary basophil adenoma) or Cushing's syndrome (most commonly due to exogenous steroid administration) 41, 42 . GR are also located peripherally, for example in subcutaneous and visceral fat deposits, and it should come as no surprise that...

Leptin Receptors

2 Historical Perspectives on the Discovery of 4 Regulation of Leptin Production and Receptor 5 Leptin Receptor 6 Obesity and Leptin 7 Leptin Signalling and Reward Pathways in the Control of 8 Pharmacological Modification of Leptin Abstract The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development....

Sources of Estrogens in Human Breast Tissue

3) 17 -estradiol hydroxysteroid dehydrogenase that preferentially reduces estrone to 17 -estradiol in tumor tissues (Fig. 3) 54,55 . 17f-Hydroxysteroid dehydrogenases (17f-HSD) belong to a family of HSD enzymes that are involved in the interconversion of the oxidized form and the reduced form of steroid hormones. Members of HSD family include 3f-HSD that catalyze the conversion of 3f-hydroxy-5-ene-steroids (e.g., pregnenolone) to corresponding 3-keto-4-ene-steroids (e.g., progesterone), 11f-HSD that catalyze the conversion of glucocorticoids and their inactive metabolites, and 17ff-HSD that catalyze the oxido-reduction at carbon 17 of C18 and C19 steroids 82-84 . There are 7 types of 17f-HSD that have been characterized so far 84-88 . Type I 17f-HSD, which is expressed mainly in the placenta, ovary and breast, catalyzes the reduction of estrone to 17f-estradiol, the most potent estrogen 89-92 . Expression of type I 17f-HSD has also been reported in human breast carcinoma, but its...

Neuroendocrine Disorders In Major Depression And Irs Activation

Major depression is accompanied by HPA-axis hyperactivity, HPT-axis alterations, such as lower basal TSH concentrations, and serotonergic disturbances. The most consistently reported signs of HPA-axis hyperactivity in major depression are endogenous hypercortisolemia and the failure to suppress plasma Cortisol with the 1 mg DST (review Maes et al., 1993a). The most consistent sign of HPT-axis dysfunction in depression is lower basal TSH (review Maes et al., 1993a). There is converging evidence that disorders in peripheral and central serotonin (5-HT) activity are implicated in the pathophysiology of major depression (review Maes & Meltzer, 1995) i) dysfunctions in the central presynaptic 5-HT neurons, which are, in part, related to a lowered avail ability of plasma L-tryptophan and (adaptive ) changes in postsynaptic receptors such as increased number, affinity or responsivity of postsynaptic 5-HT2 receptors and downregulated or desensitized postsynaptic 5-HT1A receptors....

On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

It is well known that genetic and environmental factors interact to favor weight gain, changes which disrupt metabolism. The body fat stores are normally maintained within a narrow range by energy homeostasis. This process is controlled by the brain regions, such as hypothalamus, that control appetite and energy balance in addition to peripheral signaling systems that monitor energy stores. Glucose, free fatty acids, insulin and leptin are examples of the signaling molecules that activate the hypothalamus thereby controlling the metabolic rate and the desire to eat. Obesity does not simply arise from the passive accumulation of excess body weight but is an active adaptation to the elevation of body fat. Clearly, the genetic background of the individual contributes to the variation in the response to elevated body fat which helps to explain why some individuals are protected against weight gain while the majority is not despite the fact that they live in the same environment and eat...

Nuclear Hormones Focus On Steroids

In contrast to the other neuroactive compounds we have discussed thus far, many hormones (including cortisol, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane because of their lipophilic composition (Kandel et al. 2000). Retinoic acid (vitamin A) has recently been shown to be involved in sleep, as well as learning and memory formation (Drager 2006). Nuclear receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Approximately 50 nuclear receptors are known to exist, and their structure is defined by a number of signature functional domains. Generally, nuclear receptors comprise an amino-terminal activation function, the DNA-binding domain, a hinge region, and a carboxy-terminal ligand-binding domain containing a second activation function (Kandel et al. 2000). Upon activation by a hormone, the steroid receptor-ligand complex translocates to the nucleus,...

An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

Adipose cells function not only as energy storage vessels but also as sources of regulatory molecules. One such regulator is the small protein leptin, which after secretion by fatty tissue travels to the brain where it normally induces a signal to decrease food intake. Another regulator is adiponectin, which increases insulin sensitivity, decreases glucose production in the liver, and increases glucose uptake by the muscle, all of which are antidiabetic activities. Adiponectin also decreases circulatory lipid and cholesterol and is anti-inflammatory. Excess body fat (especially abdominal fat) is associated with deregulation and abnormal function, including diminished adiponectin secretion and increased production of the proinflammatory TNF-a. The dysfunctional behavior of adipocytes in excessively heavy or obese individuals may be a consequence of several factors, including inflammation due to macrophage infiltration, cumulative damage by reactive chemical fragments and disregulation...

Alterations in Physiological Function Circardian Rhythms Sleep Pain Perception and Appetite

As part of circadian effects, there are normal 24-h fluctuations in neuroendocrine secretion, especially cortisol, growth hormone, TSH, and melatonin, as already noted above. These hormonal systems are often disrupted in depression thought to be due to heightened arousal. With shorter daylight hours, some individuals who experience the aforementioned have recurring autumn and winter depression (seasonal affective disorder, SAD) thought to be related to phase delay in the sleep-wake cycle (186, 188). Since sleep is related to endocrine function and depression, it is interesting that deep sleep has an inhibitory influence on the HPA axis. Activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. A 24-h increase of ACTH and cortisol secretion can result in insomnia, consistent with a disorder of CNS hyper-arousal (192). In addition, elevated CRF in depressed patients can cause a hyper-arousal in some brain regions that can be observed by...

HT2CRMediated Regulation of Hypothalamic PituitaryAdrenal HPA Axis

Using constitutive 5-HT2CR - Y and wild-type mice, Heisler and colleagues (Heisler et al. 2007b) demonstrated that 5-HT2CRs controlled the serotonin-evoked release of cortisol-releasing hormone (CRH) from the hypothalamic paraventricular nucleus (PVN). In hypothalamic slice preparations, infusion of the serotonin transporter inhibitor d-fenfluramine (which will increase extracellular serotonin concentrations) as well as m-chlorophenylpiperazine (mCPP), a nonselective 5-HT2C 1BR agonist, increases CRH release in slices taken from intact mice. However, neither drug evokes increased CRH release in slices taken from constitutive 5-HT2CR - Y mice. Furthermore, baseline PVN CRH expression (as measured by in situ hybridization studies against CRH message) is decreased in mutant mice compared with wild-type controls. Interestingly, there were no phenotypic differences observed in the diurnal variation of plasma cortisol, while d-fenfluramine and mCPP increased plasma cortisol only in intact...

Proteins Secreted by Visceral Adipose Tissue

Visceral adipose tissue is much more than a storage medium for excess energy. This realization came with the discovery in 1994 of leptin and its wide-ranging activities, which include reduction of appetite, angiogenesis, hematopoiesis, and bone formation 48-50 . Visceral adipose tissue is now recognized as an endocrine organ that releases a large number of biologically active molecules

Immune Activation In Treatment Resistant Depression

There are findings that suggest the involvement of HPA axis hyperactivity in the pathogenesis of TRD. Christiansen et al. (1989) found poor response to antidepressant treatment in major depressed patients with high spontaneous Cortisol levels. Others (Mc Leod, 1972 Amsterdam et al., 1983, 1994) observed a poor response to tricyclic antidepressants in patients displaying pathological responses on the dexametha-sone suppression test (DST). Moreover, the findings of Murphy et al. (1991) and of

Individuals with Bipolar Disorder at Risk for Metabolic Disorders

Intrinsic neuroendocrine features of BD may lead to somatic metabolic dysfunction. In both the depressive and manic phases of BD, there is a positive association with chronic stress and elevated cortisol 23 . These abnormalities, along with frequent hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, could potentially contribute to the higher prevalence of MetS. Chronically elevated glucocorticoids from HPA hyperactivation impedes glucose uptake by insulin, which in turn promotes metabolic dysfunction and cardiovascular disease 24 . Dysregulation of the HPA axis is also associated with obesity and elevated levels of leptin, a hormone that mediates central regulation of body mass, suggesting that the obesity may be due to inefficient leptin signaling and decreased feelings of satiety 23 . Another consequence of elevated cortisol is increased activity of lipoprotein lipase, which increases the amount of adipose tissue 25 . Elevated cortisol secretion also causes IR in...

HT2CR Mutant Mice Demonstrate a Metabolic Syndrome Consistent with Type II Diabetes

Prior to the development of obesity (but in the context of ongoing hyperphagia), young constitutive 5-HT2CR - Y mice have normal serum glucose, insulin, triglyceride, free fatty acid, corticosterone, and leptin concentrations. A separate study revealed no phenotypic differences in hepatic expression of peroxisome proliferator-activated receptor (PPAR) a and g, two transcription factors with key roles regulating lipid metabolism and energy balance (Memon et al. 2000). By 9 months of age, constitutive 5-HT2CR - Y mice are significantly more obese than wild-type littermates and demonstrate increased hepatic expression of both PPAR-a and PPAR-g. In these mice, no differences were noted in serum glucose, insulin, triglyceride, free fatty acid, corticosterone, or leptin concentrations. However, constitutive 5-HT2CR - Y mice older than 9 months are much less responsive to 3 days of leptin treatment, showing less blunting of food intake and less short-term decline in body weight. These...

HT2CRMediated Effects on Sleep and Entrainable Rhythms

Metabolic regulators of energy expenditure, including responsiveness to insulin and leptin signaling, tissue energy reserves, and baseline sympathetic tone. Recent studies also demonstrate that deficits in 5-HT2CR function alter both light and food entrainable circadian rhythms and change the quality of many sleep parameters.

Cytokines And The Hpa Axis In Major Depression And

In 60 major depressed inpatients from the Department of Adult Psychiatry in Poznan, all Caucasians with and without melancholia, the DST test was performed (Sluzewska et al., 1995b). Among those patients with an abnormal DST response, the concentrations of AGP were significantly higher than in the DST suppressors. Pathological results were observed in 33 of the patients and among them 38 suffered fromTRD. In our previous study, a significant correlation between morning plasma Cortisol levels and levels of AGP was found in the depressed patients, which could suggest an effect of glucocorticoides on AGP synthesis (Sluzewska and Rybakowski, 1993). Recent data obtained from 33 TRD patients (Sluzewska et al., 1997c) reveal a significant positive correlation between the morning plasma Cortisol levels and the plasma concentrations of IL-6, sIL-2R, AGP, ACT. Further, Maes et al. (1995c) found positive correlations between IL-6, as well as sIL-2R, and Cortisol in major depressed patients, and...

Regulation of endocannabinoid levels what is the target biosynthesis or degradation

In rat hypothalamus following systemic administration of leptin (upstream of DAGL) In the mouse uterus (by leptin) In the mouse uterus (by leptin) In lymphocytes stimulated with leptin or progesterone In the mouse uterus (by leptin) 2-AG, but through different regulatory strategies. This is the case of leptin, which causes down-regulation of AEA levels in the blood and uterus via up-regulation of FAAH expression, whereas it provokes a decrease of 2-AG levels by enhancing its degradation in the uterus and by inhibiting its biosynthesis in both the hypothalamus and the uterus (Di Marzo et al. 2001 Maccarrone et al. 2005). Finally, the possibility that COX-2 over-expression during certain pathological states, such as inflammation and colon carcinoma, may contribute to regulating endocannabinoid levels has not been investigated yet. Although the endocannabinoid membrane transporter has not been cloned to date, this putative protein too has been shown to be subject to regulation. In...

Table 1510 Recommended investigations in suspected CFS patients

Full haemogram, erythrocyte sedimentation rate, C-reactive protein, serum ferritin and vitamin B12 levels Glucose, urea and electrolytes, liver function tests (bilirubin, transaminases, GGT) CK, TSH Morning plasma cortisol or 24-hour urinary cortisol Autoantibodies for ANA and rheumatoid factor Urine dipstix for protein (if plasma or urinary cortisol is low)

L Protease Inhibitors PIs

Each of the protease inhibitors that have been studied to date has a low incidence of side effects that appear to be class related (Kaul et al., 1999). These rare adverse reactions include hyperlipidemia, lipodystrophy, hemo-lytic anemia, hyperglycemia, and spontaneous bleeding in hemophiliacs. Each reaction has been associated with each of the protease inhibitors. The PI-associated hyperlipidemia is usually an elevation of the triglycerides. In PI-associated lipodystrophy, patients develop aberrant fat deposits around their waists and on the back of their necks (''buffalo humps''). This problem is more cosmetic than medical and may resolve with discontinuation of the PI. PI-associated hyperglycemia can be mild or can present as ketoacidosis with new onset diabetes mellitus.

Genetic Manipulations

Major depression is a heritable disorder that likely involves multiple genes, each with small effects (Wong and Licinio 2001). Targeted gene deletions and gene transfers in animal models are beginning to elucidate the functional significance of potentially relevant genes (Insel 2007). Consider, for example, dysregulation of the HPA axis evinced in depression by an increase in cortisol levels (see Chapter 45, Neurobiology of Mood Disorders). Receptors for cortisol are densely expressed in the prefrontal cortex (Webster et al. 2002), where they function as transcription factors that regulate gene expression (Chrousos and Kino 2005). Hundreds of genes in prefrontal cortex appear to be differentially expressed in humans with a history of major depression based on postmortem analysis of whole-genome microarray data (Choudary et al. 2005 Evans et al. 2004 Iwamoto et al. 2004 Sequeira et al. 2006). Genetic manipulations of receptors for Cortisol are not yet feasible in human patients but...

Growth Metabolism and the Stress Response

The hormones secreted by the thyroid thyroxine (T4) and triiodothyronine (T3) and adrenal (cortisol and adrenaline) tissues are identical in both fish and mammals. In fish, however, these tissues do not form discrete glands the thyroid is scattered around the ventral aorta, while adrenal tissue is dispersed within the kidney. This makes it very difficult to measure the changes induced in their structure by chemical pollutants. The hormones of the thyroid regulate general metabolic rate, growth and possibly embryonic development, while those of the adrenal are involved in the stress response, osmoregulation and carbohydrate metabolism. Growth in fish is continuous and does not cease at puberty as in mammals. Fish size is therefore not only dependent on secretion of growth hormone by the pituitary gland as in mammals, but on age and the rate of metabolic activity and energy utilisation as determined by both the thyroid and interrenal glands. Thyroid and adrenal activities are also...

Actions of VP and OT in Nonneural Tissue Sites and Glucose Regulation Role in Memory Processing

VP and OT actions in nonneural tissues and within the brain have an important role in glucose storage and utilization. VP promotes eating behavior and or increased hepatic production of glucose after hypoglycemia (Baylis and Robertson, 1980 Keppens and de Wulf, 1974), and inhibits food intake in association with food satiation (Kow and Pfaff, 1986). Similarly, an OT neuronal system of PVN origin projects to brainstem ANS centers and regulates feeding, digestion, and metabolism (McCann and Rogers, 1990 Sofroniew and Schrell, 1981 Tribollet et al., 1988). This OT pathway appears to inhibit feeding and associated digestive processing in response to food satiation or gastric distress (Olson et al., 1991 Verbalis et al., 1986), but promotes feeding, digestion, and anabolic metabolism (tissue growth and fat storage) during pregnancy and lactation (Uvnas-Moberg, 1989, 1994).

Endocannabinoid System ControL of Energy BMAnce

In the central nervous system (CNS) endocannabinoids are synthesized by neurons in response to depolarization (Freund et al., 2003), and act as neurotransmitters mediating a retrograde signal to the presynaptic site where they inhibit GABA and glutamate release in a CB1 receptor-dependent mechanism (Wilson and Nicoll, 2002). Interestingly, endocan-nabinoids are likely released immediately after biosynthesis and still now no evidence exists for their storage in secretory vesicles. Endocannabinoid production increases between meals and rapidly decreases following access to food suggesting a direct modulation of feeding behavior (Kirkham et al., 2002). Endocannabinoids, by interacting with CB1 receptors, induce a dose-dependent orexigenic effect. The direct administration of AEA into the ventromedial nucleus of the hypothalamus causes a general hyperphagic effect blocked by administration of CB1 antagonists (Jamshidi and Taylor, 2001). In mouse models of obesity such as ob ob and db db...

Posttraumatic Stress Disorder

Given the stress-related etiology of PTSD, it was expected that PTSD patients would show HPA axis abnormalities similar to those seen in depressed patients or chronically stressed animals, but this has not always been the case. An initial study (Mason et al. 1986) found that urinary free cortisol (UFC) excretion was lower in PTSD than in major depression. However, another study (Pitman and Orr 1990) found increased UFC excretion in outpatient PTSD veterans compared with combat-exposed control subjects without PTSD. Since then, there have been various findings, but the most comprehensive studies of PTSD, those by Yehuda and colleagues (for a review, see Yehuda 2002), continue to show low cortisol and enhanced cortisol suppression in response to dexamethasone in combat veterans with PTSD. Interestingly, the presence of comorbid major depression does not change the neuroendocrine picture. The main criticism of this body of work is that the sample comprised only male combat veterans and...

The Therapeutic Problem

Asthma is characterized by variable obstruction of the airways that is a consequence of inflammation in the lungs. There are two distinct causes of airways obstruction. The most obvious is contraction of bronchial muscle, which responds rapidly to epinephrine and other b-adrenergic bronchodilators. The most dangerous is physical occlusion of the airways caused by osmotic swelling and other derangements of bronchial mucosal structure and function. It is not relieved by bronchodilators and is reliably prevented or reversed only by cortisol and other glucocorticoid steroids. Bronchodilators are effective in less severe asthma because bronchoconstriction is the dominant cause of airway obstruction at this stage. As asthma worsens, Mucosal damage (prevented 01 reversed by Cortisol) Causes of airway obstruction in asthma, effects of epinephrine and cortisol on them, and relationship between the severity of asthma and the bronchodilating effect of inhaled b-adrenergic bronchodilators. If...

Ovarian Structure and Hormones

Synthesis of the steroid hormones testosterone and 17,20 P is identical in both ovary and testis, and dependent upon the functional integrity of both the steroid producing enzymes and the receptors for pituitary gonadotrophins. Xenobiotics that affect the components of the testis will therefore also have an effect on the ovary. Inhibition of ovarian steroid synthesis has been demonstrated for the heavy metals cadmium and lead, and the pesticides DDT, y-BHC, malathion, metacid-50 and carbaryl. Hormone levels were also depressed in plasma of fish exposed to the effluent of pulp mills or taken from the Great Lakes and other areas rich in PCBs and PAHs. Male and female gonads differ in that only the ovary has an active aromatase enzyme that converts testosterone to estradiol. Inhibition of this ovarian aromatase activity in female fish will decrease estrogen synthesis, and have consequential effects on the ability of its liver to synthesise yolk proteins, leading to retarded growth of the...

Potential Pathophysiological Mechanisms for Glucose Elevation

Glucose levels and other parameters have tended to show abnormalities in treatment-naive subjects however, not all studies are consistent in this finding 29, 63-66 . A consistent finding from the Dublin group has been elevation in glucose levels and increased abdominal fat in their treatment-naive subjects 29, 42, 43 . The underlying mechanism has, however, remained undefined. Recently, it has been proposed that deficient IGF-1 levels may underlie insulin resistance in schizophrenia 67 . In a relatively large study of 88 subjects, subjects with schizophrenia had higher insulin levels and greater insulin resistance than controls with evidence of lower IGF-1 levels. Insulin levels were elevated even after controlling for cortisol. IGF-1 has been postulated as being involved in the pathogenesis of schizophrenia 68 . Similarly, in 45 first-episode subjects either treatment-naive (n 15) or receiving antipsychotic treatments for mostly less than 4 weeks with a normal baseline BMI of 24.29...

Effects of Depression and Stress on Acquired Immune Lymphocyte Responses

In psychiatry, the practical import of connections between brain outflow pathways and the immune system has been best documented in the effects of stress-related disorders, especially major depression, on immune functioning. Despite a significant degree of heterogeneity across individual studies, significant evidence suggests that patients with major depression demonstrate a number of immune changes similar to those seen in individuals undergoing chronic and or severe stress (Herbert and Cohen 1993 Zorrilla et al. 2001). This is hardly surprising, given the many indices of stress system hyperactivity that are apparent in patients with major depression, including increased corticotropin-releasing hormone (CRH) and cortisol production (Pariante et al. 1995) and augmented sympathetic nervous system (SNS) activity as manifested in part by increased peripheral blood catecholamines (Veith et al. 1994 Wong et al. 2000). Enumerative immune changes shared by major depression and chronic severe...

Hypothalamic PituitaryAdrenal Axis

System depend on numerous factors, including the immune compartment that is assessed, the element of the HPA axis being evaluated (i.e., CRH vs. Cortisol), and the duration and timing relative to the immune response and stressor application. Thus, for example, glucocorticoids are known to acutely diminish CD4 cell counts in the blood however, at the same time, glucocorticoids enhance CD4-mediated DTH reactions in the skin, through their effects on lymphocyte trafficking (Dhabhar 1998). Moreover, different HPA axis elements demonstrate divergent immune system effects. For example, the end result of CRH-induced HPA axis activation is proinflammatory cytokine suppression, and yet studies demonstrate that the direct effect of CRH on proinflammatory cytokine production may be stimulatory (Labeur et al. 1995 Paez Pereda et al. 1995).

Pharmacological Properties

The hormone leptin was discovered in 1994 its name is derived from the Greek word for thin, leptos. Like other hormones, leptin is secreted in a pulsatile manner and shows a diurnal variation with a peak during the night. Lack of leptin signaling due to a mutation of leptin (e.g., ob ob mouse) or the leptin receptor (lepr) (e.g., db db mouse) in rodents and humans results in increased food intake, reduced energy expenditure, and severe obesity. Leptin replacement reverses many of the phenotypes of leptin-deficient mice. However, it was quickly apparent that an absolute leptin deficiency is an extremely rare cause of human obesity. Plasma leptin levels are elevated, rather than reduced, in the majority of obese subjects and plasma leptin levels are highly correlated with total fat mass. Thus, resistance to leptin action appears to be a more likely cause of human obesity. Leptin also plays a role in the regulation of neuroendocrine function. Mutations in the leptin gene are associated...

Other Acid Suppressants And Cytoprotectants

Rebamipide acid) is used for ulcer therapy in parts of Asia. It appears to exert a cytoprotective effect both by increasing prostaglandin generation in gastric mucosa and by scavenging reactive oxygen species. Ecabet (gastrom 12-sulfodehydroabietic acid monosodium), which appears to increase the formation of PGE2 and PGI2, also is used for ulcer therapy, mostly in Japan. Carbenoxolone, a derivative of gly-cyrrhizic acid found in licorice root, has been used with modest success for ulcer therapy in Europe. Its exact mechanism of action is not clear, but it may alter the composition and quantity of mucin. Unfortunately, carbenoxolone inhibits the type 2 isozyme of 11 -hydroxysteroid dehydrogenase, which protects the mineralocorticoid receptor from activation by cortisol in the distal nephron it therefore causes hypokalemia and hypertension due to excessive mineralocorticoid receptor activation (see Chapter 59). Bismuth compounds (see Chapter 37) may be as effective as cimetidine in...

Role Of Permeation Enhancers

There is currently keen interest in development of a variety of different classes of enhancers that promote increased drug permeation by the trans-cellular and or paracellular route see recent reviews (75,76,84-86) . For instance, Zhang et al. (87) employed electron spin resonance and confocal laser scanning microscopy to study the permeation of recombinant hirudin-2 across rat nasal tissue. It was found that chitosan appeared to promote the paracellular pathway, ammonium glycyrrhizinate invoked transcellular transport, and hydroxyl-propyl-b-cyclodextrin was associated with both mechanisms. As another example, Arnold et al. (88) investigated the alkylglycoside tetrade-cylmaltoside and described the in vitro internalization of coadministered therapeutic proteins including insulin, leptin, and somatotropin, consistent with a transcellular transport mechanism with this excipient at high excipient concentration, cellular morphological changes were observed.

The MR Mediates Effects of Aldosterone and Corticosterone in a Limited Set of Target Organs

Of sodium reabsorption (Funder, 1993). In contrast, in the hippocampus the MR participates in the control of neuronal activities ( Joels and deKloet, 1994). As the MR is able to bind both mineralocorticoids and glucocorticoids with approximately equal affinity, it is important to prevent access of cortico-sterone to the MR in aldosterone target tissues. In kidney and colon this is achieved through expression of the enzyme 11 -hydroxysteroid dehydrogenase type II (11 OHSDII), which enzymatically inactivates corticosterone (Funder etal., 1988). Therefore, in these epithelial tissues the MR is predominantly activated by aldosterone. However, in the hippocampus no such protective mechanism exists. Consequently, because of the much higher serum concentration of corticosterone, the MR in the hippocampus is mainly occupied by this hormone.

Activation of Endocannabinoid Biosynthesis

Mass spectrometry analyses provided direct biochemical evidence that GCs robustly activate the biosynthetic pathways leading to the release of both AEA and 2-AG in the PVN even when synaptic activity is suppressed (Malcher-Lopes et al., 2006). Both the increase on tissue levels of endocan-nabinoids triggered by GCs and GSE, the synaptic effect mediated by the endocannabinoids, were completely blocked by the cytokine-like adipocyte peptide leptin (Malcher-Lopes et al., 2006). Leptin has been shown to prevent fasting-induced hyperphagia in rats by blocking the rise on hypothalamic endocannabinoid levels that normally takes place during caloric deficit (Di Marzo et al., 2001 Kirkham et al., 2002). Leptin effect on GSE was mediated by reducing cAMP levels via phosphodiesterase 3B (PDE3B) activation, fact that conduced to the subsequent demonstration that GCs trigger the synthesis and release of AEA and 2-AG through a Gas-cAMP-PKA-dependent mechanism (Malcher-Lopes et al., 2006) (Fig....

Immune Activation Induced Hpa Changes And Depression

Several of the long-lasting immune stimulus induced alterations found in rats are also seen in depressed patients (see Table 2). As outlined above, alterations at these levels are most probably instrumental for the sensitization of the HPA system as seen in both conditions. Therefore, we hypothesize that in humans as in rats, transient activation of the immune system may result in a period of HPA sensitization and changes in CRH neurons. During this period of HPA sensitization, the ACTH and Cortisol responses to internal or external stimuli are supposedly enhanced and therefore this period reflects a state of increased vulnerability to stressors. Based on animal

The Neuro EndocrineImmune System

The steroid hormones are metabolically derived from cholesterol, and are biologically stable, lipophilic chemicals which are active at low concentrations. Many steroid hormones exist, and are generally named after their principal organ of origin or their main biological function. Because of the complexity and evolutionary history of the endocrine system, these hormones may serve several functions within different tissues of an organism. For example, the sex hormones are primarily produced by the gonads, and comprise the androgens (male hormones) and oestrogens (female hormones). These chemicals have vital roles in the control of reproductive functions such as sperm or ova development, and the development and maintenance of secondary sexual characteristics. During development, the balance of these hormones also plays a key role in the formation and functioning of sexually dimorphic parts of the brain (with consequent implications for sexual behaviour) and in the development of a...

Hypothalamic PituitaryAdrenal Axis Normal Physiology

From a physiological perspective, the response to stress is mediated by the HPA axis. A full description of this regulatory process is beyond the scope of this chapter and the reader is referred to Charmandari et al. 1 and Tsigos et al. 2 for a more comprehensive review. One of the primary mammalian responses to stress, be it psychological or physical, is activation of the HPA axis. In essence, the stressor stimulates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus. CRH in turn causes the production and secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary gland. CRH is the prime secretagogue of ACTH though in situations of chronic stress this role is probably deferred to arginine vasopressin (AVP). ACTH travels to the adrenal glands where it stimulates the production and release of glucocorticoids (GC) such as cortisol. This series of hormonal releases occurs as a cascade and is termed the...

Pathogenesis Behind These Associations

The exact mechanism(s) behind the association between obesity and some cancers is unknown. Obesity itself develops via complex mechanisms involving interactions between heredity and lifestyle changes that include nutritional and exercise considerations. Even the location of the fat deposits may provide clues as to the pathogenesis, as described below.38 The general thought is that augmented fat deposits lead to hormonal imbalances. For example, high levels of estrogens contribute to the proclivity toward cancer. The increased risk of breast cancer after menopause in obese women is believed to be due to increased levels of estrogens.39 Prior to menopause, the ovaries are the primary source of estrogen. After menopause, when ovaries stop producing estrogen, fat tissue becomes the primary source.39 Logic dictates that more fat leads to more circulating estrogens and, hence, an increase in risk.

Testing of HPA Axis Reactivity

Cortisol, the human's principal glucocorticoid, binds in plasma to serum albumin and with higher affinity to corticosteroid binding globulin or transcortin. Hence, total cortisol can be measured as index for adrenocortical output free cortisol is considered to be the biologically active fraction. Currently, the free cortisol concentration is often determined in saliva, which can be obtained by a much less stressful procedure than blood via venipuncture. In 24 h urine cortisol and 17-ketosteroids (17-OHCS) are measured and are an index for daily production. Basal values of cortisol are often reported, but these levels must be judged with care. In single measurements, hourly pulses of the hormone may produce variable data unless temporal patterns are measured. Moreover, the amplitude of the cortisol pulse displays a strong circadian rhythm producing high levels of the hormone during awakening and low levels from usually 11.00 p.m. to 5.00 a.m. Finally, 30 min after awakening a sharp...

Post Traumatic Stress Disorder

Core features of HPA axis changes in PTSD include low basal cortisol secretion and enhanced negative feedback control of the HPA axis (Yehuda 2002). The enhanced negative feedback was found using low-dose dexamethasone (0.25 mg) or metyrapone tests. Blunted ACTH responses to CRF stimulation are explained by downregulated CRFR1, possibly as a result of sustained, increased endogenous CRF levels. However, findings have not been consistent. Differences could involve disease stages, gender, genetic background, or type of trauma among others. Using the combined Dex-CRF test did not reveal HPA-axis abnormalities in PTSD patients when compared to trauma controls (also exposed to trauma but without PTSD). However, PTSD patients with a comorbid MDD showed an attenuated ACTH response compared to PTSD patients without comorbid MDD. This indicates the presence of PTSD subgroups with different HPA-axis regulation.

Anesthetic and Sedative Agents

This class of drugs generally inhibits excitatory channels (e.g., glutamate) and facilitates inhibitory channels (e.g., GABA). Ether induces a profound activation of the HPA axis with high levels of ACTH and cortisol. Halothane also induces an increase in plasma ACTH following administration without surgery in healthy volunteers. General anesthesia maintained with an isoflurane-nitrous oxide-oxygen mixture or sevoflurane is followed by a sharp increase in plasma cortisol. The combination of droperidol, a dopa-mine D2 antagonist, with an opioid analgesic induced plasma cortisol elevations. In contrast, a mixture of pro-pofol (acting at GABAA and maybe glycine and endo-cannabinoids) and remifentanyl (mu opiate receptor agonist) did not activate the HPA axis, and even blocked HPA axis responses during surgery. However, still under anesthesia with propofol, synthetic ACTH was still capable of inducing a profound cortisol plasma level elevation. Thiopental, a barbiturate acting on GABA...

Linking Between 5HT and Control of Both Food Intake and of Feeding Behavior

The involvement of MC system in the regulation of food intake and body weight is well established, and recently it has become evident that the MC system may modulate the effects of 5-HT drugs on rodent feeding behavior (Heisler et al. 2002, 2003). Heisler et al. (2006) demonstrated the role of downstream melanocortin 4 receptors (MC4R) in mediating 5-HT-induced hypophagia. Activation of both 5-HT2C and 5-HT1B receptors produces hypophagia by promoting the release of the endogenous agonist and inhibiting the release of the endogenous antagonist of the MC4R receptor. This effect appears dependent on three mechanisms. First, 5-HT inhibits orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus via 5-HT1B receptor activation. This inhibits the releases of the MC4R antagonist AgRP. Second, activation of axonal 5HT1B receptors on AgRP neuronal projections also decreases their inhibitory effect on adjacent anorexigneic pro-opiomelanocortin (POMC) neurons. This promotes the...

Contributing To Oxidative Stress In Ad

In response to physical and psychological stressors, glucocorticoids (cortisol in humans and corticosterone in rodents) are released from the adrenal gland. Based on extensive experimental data, it has been proposed that glucocorticoids promote neuronal degeneration in some brain regions in aging and AD (142). Glucocorticoids may endanger neurons by inhibiting glucose transport, thereby promoting metabolic compromise and excitotoxic injury (143). We have found that exposure of cultured hippocampal neurons to glucocorticoids increases their vulnerability to oxidative and excitotoxic insults, and to death induced by Ap (28). Our data suggest that glucocorticoids enhance disruption of calcium homeo-stasis and oxy radical production in neurons. Interestingly, there is evidence that AD patients have perturbed regulation of glucocorticoid production resulting in increased levels of circulating glucocorticoids, which could contribute to the neu-rodegenerative process.

Neural and physiological mechanisms

Decrease in whole-brain CBF, with no regional differences.32 Caffeine also modulates neural activity through its inhibitory effect on ionotropic GABA receptors33 and, like other methylxanthines, acts on serotonin and noradren-aline neurons and affects local dopamine release.31 These actions further explain its stimulating effects, which include activation of major components of the hypothalamic-pituitary-adrenal (HPA) axis response. In particular, caffeine increases adrenocorticotropin (ACTH) release at the pituitary, resulting in elevated cortisol production.34

Interaction Between The Brain And Immune System In Stress And Depression

The monoamine hypothesis of depression proposes that a deficit of brain noradrenaline (NA) and or serotonin (5-HT) may be causally involved in the symptoms of illness (Baldessarini (1975). Another theory of depression suggests that the disorder in hypothalamus-pituitary-adrenal (HPA) axis causes an increase in secretion of corti-cotropin-releasing factor (CRF), which stimulates adrenocorticotrophin hormone (ACTH) and Cortisol release (Bateman Singh, Krai, and Solomon, 1989). Recently, the macrophage theory of depression, which will be discussed in detail later in this review, has also been proposed. In this hypothesis, the abnormal secretion of some cytokines such as interleukin-1 (IL-1) and interferon-alpha (INF-alpha), results in disordered secretions of CRF, ACTH, prolactin, and Cortisol, together with a depressive state (Smith, (1991). These three hypothesis may be linked. Whatever changes in the central nervous system (CNS) or in the endocrine system occur, different aspects of...

Interleukin10 and Prednisone

Combination therapy of IL-10 and the corticosteroid prednisone may be beneficial, and the combined use of these two drugs may result in mutual dose reduction. Chakraborty et al. (34) studied pharmacokinetic interactions of a single oral dose of prednisone and SC recombinant human IL-10 in 12 healthy male volunteers. Single doses of IL-10 (8 mg kg), IL-10 with prednisone (15 mg orally), placebo with prednisone, or placebo were administered on four separate occasions with at least three-week washout periods. The results of the study indicated that prednisone had no effect on the pharmacokinetics of IL-10 or vice versa (Tables 4 and 5). Both prednisone and prednisone IL-10 treatments caused marked suppression of endogenous cortisol concentrations however, IL-10 alone was sufficient to significantly increase the 24-hour AUC of endogenous cortisol by 20 .

Genetic Studies In Humans With Obesity Or Eating Disorders

Since it became clear in mouse models that mutations in genes of the neuronal circuitry underlying energy balance can cause obesity many associations studies have been performed to identify the relevance of these genes for obesity in humans. In this part we will go into detail concerning the association studies, which show functional sequence changes, done for the genes involved in the leptin signalling pathway as described before. For the leptin gene itself, although indicated as the obesity gene after the ob ob mouse, few mutations and polymorphisms have been found, which makes the link between leptin and overweight in humans uncertain. Although a number of studies have investigated the leptin gene and its role in obesity, only one study reports on polymorphisms present in the leptin gene in obese individuals and not in average weight people. In this study both the leptin gene itself and its regulatory element were genotyped in 125 extreme obese and 86 average weight females. Three...

Psychological factors in chronic pelvic pain

A woman's response to an acute pain experience may therefore be more likely to progress to a chronic process based on a current or previous emotional experience, catastrophizing personality style, expectations, mechanism or thinking, and or habits. This process likely involves alterations in central processing. The stimulus for these alterations and mechanisms underlying the maintenance of changes in central processing without an inflammatory stimulus or nerve damage are unknown. Other factors may include alterations in the hypothalamic-pituitary-adrenal axis and cortisol levels.122,130

Adrenocortical Steroids

The adrenal cortex synthesizes two classes of steroids the corticosteroids, which have 21 carbon atoms, and the androgens, which have 19 (Figure 59-2). The actions of corticosteroids are classified as glucocorticoid (carbohydrate metabolism-regulating) and mineralocorticoid (electrolyte balance-regulating), reflecting their preferential activities. In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the main mineralocorticoid. Typically cortisol is secreted at a rate of 10 mg day whereas aldosterone is secreted at a rate of 0.125 mg day. The concentrations of cortisol in peripheral plasma are considerably higher in the morning (16 ,ug dL at 8 am) than in the late afternoon (4 ,ug dL at 4 pm) reflecting diurnal regulation, whereas the plasma concentrations of aldosterone are lower and more constant (0.01 ,ug dL) throughout the day. The daily production of cortisol can rise at least tenfold in the setting of severe stress. Estimates of potencies of...

Gonad Hormone Production

Other steroid synthetic pathways in other organs can also be affected, as plasma cortisol concentrations were suppressed in BKME-exposed fish from Jackfish Bay subjected to stress during sampling 54 . Fish exposed to environments contaminated with polycyclic aromatic hydrocarbons (PAHs), polychlo-rinated biphenyls (PCBs), or heavy metals also show a suppressed stress response as measured by plasma cortisol concentrations 54,55 . In contrast, fish exposed to pesticides can exhibit an augmented stress response and elevated plasma cortisol concentrations compared to reference fish (Orlando, Binczik, Kroll, and Guillette, unpublished data). Likewise, alligators living in a pesticide-contaminated lake exhibit similar basal concentrations of corticosterone 47 but show a more rapid response to stressful stimuli when compared to reference animals 56 .

Neuroendocrine Alterations

Hormones such as cortisol, growth hormone (GH), and thyroid hormone can be affected particularly in patients with an altered HPA axis. Studies have reported increased levels of adrenocortical trophic hormone (ACTH) and decreased levels of insulin-like growth factor (IGF-1), triiodothyronine (T3), GH, estrogen, and urinary cortisol.44

Pharmacodynamic Applications

Cortisol is secreted episodically by normal man. It was also realized that this pulsatility was not due to noise, but was actually associated with physiological processes. Indeed, the circadian clock, the interaction between hormones through feedback mechanisms, and the interaction of hormones with central and autonomic nervous systems are some of the reasons for this behavior. It has been apparent that the theory of dynamic systems is the right field in which to find useful tools for the study of hormonal systems. This has been done along two directions A Dynamic System for Cortisol Kinetics Although the detailed features of the interactions involved in cortisol secretion are still unknown, some observations indicate that the irregular behavior of cortisol levels originates from the underlying dynamics of the hypothalamic pituitary adrenal process. Indeed, Ilias et al. 514 , using time series analysis, have shown that the reconstructed phase space of cortisol concentrations of...

Immune Activation And Depression Are Both Associated With Similar Neuroendocrine Alterations

Depression is characterized by marked alterations in neuroendocrine function. In particular, dysregulation of the HPA axis has been suggested as an important aspect of the pathophysiology of depression. Patients with major affective disorders exhibit elevated serum, urinary, and cerebrospinal fluid (CSF) levels of Cortisol (Carol , Curtis, & Mendels, 1976 Sachar, Hellman, Fukushima, & Gallaghaer, 1970 Traskman,Tybring, Asberg, Bertilsson, & Schalling, 1980), abnormal 24-hr Cortisol secretory patterns (Linkowski, Mendlewicz, Leclercq, Brasseur, Hubain, Goldstein, Copinschi, & van Cauter, 1985), and non-suppression of serum Cortisol following dexamethasone administration (Carroll, Martin, & Davies, 1968 Holsboer & Barden, 1996). The excessive adrenal Cortisol secretion in depressed patients probably reflects abnormal limbic-hypothalamic activation, which results in increased production and secretion of corticotrpin-releasing hormone (CRH) (Gold, Chrousos, Kellner,...

Adaptive And Maladaptive Aspects Of Immunologic Allyinduced Depression

Both syndromes are also associated with alterations in immune functions, including abnormal levels of lymphocytes, hyperactive immunological responses, high levels of antibodies to Epstein-Barr Virus, and other viruses, and impaired regulation of cytokine secretion (Buchwald & Komaroff, 1991 Komaroff & Buchwald, 1998). Blood levels of Cortisol, which normally limits the extent of brain cytokine production and their behavioral impact (Goujon, Parnet, Laye, Combe, Kelley, & Dantzer, 1995 Johnson et al., 1996), are lower in these patients (Cleare, Bearn,Allain, McGregor, Wessely, Murray, & O'Keane, 1995). Thus, CFS and PVFS seem to involve impairment in at least one of the mechanisms responsible for down regulating the immune system, along with its psychological effects, following recuperation from a viral infection.

Npy And Galanin Link The Dietary Aspects Of The Kd To Its Anticonvulsant Effect A Model

A model in which NPY and galanin might mediate the anticonvulsant effect of the KD is depicted in Figure 1. The low glucose content of the KD decreases circulating leptin and insulin levels, which in turn leads to the increased expression of NPY and galanin, the activation of their respective neurons, and enhanced peptide release. Ingestion of large amounts of fat coordinately increases galanin expression. The inhibition of excessive neuronal excitability by NPY and galanin thus contributes to the anticonvulsant effect of the KD. Some empirical evidence exists that supports this model. First, the administration of a calorically restricted KD indeed results in starvation-like conditions that reduce body weight and inhibit growth (43) and would be expected to promote NPY (and perhaps galanin) expression. Second, reduced insulin and leptin levels are observed in people maintained on the KD (44-48), which again would likely increase the expression of orexigenic neuropeptides....

Genetic and related effects

CYP3A4 phenotype, as judged by urinary Cortisol metabolite ratios, was also not associated with adduct level. The main factors affecting the level of aflatoxin-albumin adducts were place of residence (rural areas higher than urban areas) and season of blood sample collection (dry season higher than wet season) (Wild et al., 2000). Kensler et al. (1998) also found no association between aflatoxin-albumin adducts and GSTM1 genotype in 234 adults from Qidong County, China.

Animal Experiments 1 Rhythms that Can be Measured

Besides analyzing the rhythmic nature of seizures, investigators can also examine other well-characterized rhythms and compare these rhythms to the seizure rhythm. Examples of other rhythms studied include locomotor activity (wheel running), body temperature, heart rate, feeding, and drinking. In the past, the easiest rhythms to measure were wheel running activity or feeding and drinking rhythms. However, with the advent of implantable transmitters (Table 12.1), generalized activity, body temperature, and heart rate can be measured in the same animal with relative ease. More difficult rhythms to determine include plasma levels of cortisol or melatonin, although some investigators have routinely measured these hormones with the use of indwelling venous catheters.

Do The Brain Action Of Cytokines And The Symptoms Of Depression Share Common Mechanisms

The analogy that has been drawn between brain effects of cytokines and symptoms of depression appears to be similar in its principle to the one that was proposed some time ago for CRH and depression. Like the macrophage theory of depression, the hypothesis of a causal role of CRH in the pathophysiology of depression has been built up on the convergence of two sets of data. At the experimental level, CRH infusion into the brain of laboratory rodents has been shown to induce depression-like signs, including sleep disorders, reduced appetite, decreased sexual behavior, and anxiety. At the clinical level, depressed patients are known to have an hyperactive HPA axis, as evidenced by higher levels of CRH in the cerebrospinal fluid, increased plasma Cortisol levels, and resistance to the dexamethasone suppression test. In line with the CRH hypothesis of depression, and as proposed by Miller et al in their chapter, proinflammatory cytokines would play a causal role in depression mainly...

Rhythms that Can be Measured

Virtually all of the rhythms that can be determined in animals can also be determined in humans. However, the methods for collecting these rhythms are quite different. General activity can be determined with the use of a wrist watch sized monitor (Ambulatory Monitoring, Inc., Ardsley, NY) (Table 12.1). Body temperature and heart rate can be assessed by placement of specific transceivers that relay the information to dedicated computers. Subjects can also have sequential blood samples collected for determination of hormonal rhythms, such as cortisol or melatonin.11

Overall Conclusions And Hypotheses

Thus, glucocorticoids inhibit CRF-41 synthesis and release and ACTH synthesis and release. Estradiol, in its positive feedback mode, stimulates LHRH synthesis and release. However, whether synthesis and release are mechanistically linked has not been established. Third, all feedback loop variables also operate in the same direction. Thus, glucocorticoids inhibit CRF-41 release and pituitary responsiveness to CRF-41. Estrogen in its negative feedback mode inhibits pulse frequency and amplitude and pituitary responsiveness. In its positive feedback mode, E2 stimulates LHRH release and pituitary responsiveness to LHRH. The priming effect of LHRH, a major component of the E2 positive feedback mechanism for the ovulatory LH surge further potentiates pituitary responsiveness and coordinates it with LHRH release so that both reach a peak simultaneously. Both the HPA and HPG depend on circadian drive, probably generated by the SCN. In the HPA this generates the...

Immune Alterations In Depressed Patients

Compared to healthy out-patient controls, although this reduction was not correlated with severity of depression as reflected by Hamilton scores. Despite the well known inhibitory action of glucocorticoids on immune activity, the decrease in lymphoprolif-eration was not related to the HPA axis hyperactivity (Cosyns, Maes, Vandewoude, Stevens, De Clerk, & Schottel, 1989 Kronfol & House 1985), as assessed by the dexamethasone suppression test (DST). Indeed, depression of lymphoproliferation was equally found in both DST positive and DST negative patients (Albrecht, Helderman, Schlesser, & Rush, 1985). However, others authors (Maes, Bosmans, Suy, Minner, & Raus, 1989 Maes, Bosmans, Suy, Vandervorst, Dejonckheere, Minner, & Raus, 1991) did find an inverse correlation between lymphocyte proliferation and Cortisol levels. The decrease of mitogenesis has also been found to be inversely correlated to the turn-over of norepinephrine and the age of the patients (Maes et al.,...

Mood Stabilizers and Impact on Insulin Resistance in Women with Bipolar Disorder

Women with BD are often treated with psychotropic agents, including mood stabilizers, atypical antipsychotics, and antidepressants, whose effects on reproductive function and IR are not fully understood. Medications may impact weight and endocrine abnormalities in a variety of ways that contribute to IR. For example, it has been theorized that valproate can influence the development of menstrual abnormalities by decreasing estrogen levels, increasing luteinizing hormone and increasing testosterone 54 . The increase in testosterone can lead to an arrest in maturation of ovarian follicles, leading to the development of polycystic ovaries. Additionally, valproate may cause an increase in leptin resulting in increased body weight 54 , or lead to glucose-stimulated insulin secretion by pancreatic cells 55 . Weight gain itself, not specific to valproate use, may lead to menstrual abnormalities or IR. In our studies, we demonstrated a correlation between BMI and both testosterone and insulin...

Depressionassociated Alterations In The Hpa System

Functional changes often referred to as dysregulations of the HPA system have been extensively documented in patients with depression (Akil & Ines Morano, 1995 Post & Weiss, 1995 Holsboer & Barden, 1996). These include increased episodes of ACTH and Cortisol secretion, elevated mean Cortisol levels in the blood and increased free urinary Cortisol levels. Various observations from both clinical and experimental animal studies support a causal link between dysregulation of the HPA system and psy-chopathology. Increased episodes of enhanced Cortisol levels will lead to overexposure of the brain to this glucocorticoid and will affect the functioning of limbic forebrain structures including the hippocampus that are involved in processing of cognitive stimuli and the regulation of mood, learning, and memory processes, as well as aminergic systems in the brain stem that play a role in arousal and appraisal of environmental stimuli (De Kloet & Joels, 1996 Joels, 1997)....

Glucocorticoids With Moderatetolow Salt Retention

Cortisone acetate, is the 21-acetate of naturally occurring cortisone with good systemic anti-inflammatory activity and low-to-moderate salt-retention activity after its in vivo conversion to hydrocortisone acetate. This conversion is mediated by 11j-hydroxysteroid dehydrogenase. It is used for the entire spectrum of uses discussed previously under the heading, Therapeutic Uses of Adrenal Cortex Hormones collagen diseases, Addison disease, severe shock, allergic conditions, chronic lympho-cytic leukemia, and many other indications. Cortisone acetate is relatively ineffective topically, mainly because it must be reduced in vivo to hydrocortisone. Its plasma halflife is only about 30 minutes, compared with 90 minutes to 3 hours for hydrocortisone.

Role of Hippocampus and Amygdala in Glucocorticoid Negative Feedback

Possible Role of 11fi-Hydroxysteroid Dehydrogenase 1 lp-Hydroxysteroid dehydrogenase (1 lp-OHSD) rapidly converts the active glucocorticoids, Cortisol, and corticosterone to inactive 11-keto products, cortisone and 11-dehydrocorticosterone, respectively. In the kidney, this mechanism is thought to prevent mineralocorticoid excess, since both Cortisol and corticosterone bind to mineralocorticoid receptors with high affinity and are also present in the systemic circulation at concentrations about 1000-fold greater than aldosterone (Edwards et al., 1988). High concentrations of 1 lp-OHSD are also present in the PVN (Seckl et al., 1993), and we recently demonstrated that administration of glycyrrhetinic acid, an inhibitor of 11 (3-OHSD, resulted in a significant decrease in CRF-41 release into hypophysial portal blood. These data suggest that 1 lp-OHSD may play a part in determining the strength of the glucocorticoid feedback signal on CRF-41 neurons (Seek et al., 1993). However, in...

What Would Be The Logical Primary Metabolite Of A Phase I

Pharmaceutical Chemistry Images

Inducers of microsomal enzymes also may enhance the metabolism of endogenous compounds, such as steroidal hormones and bilirubin. For instance, phenobarbital can increase the metabolism of cortisol, testosterone, vitamin D, and bilirubin in humans.508,509 The enhanced metabolism of vitamin D3 induced by phenobarbital and phenytoin appears to be responsible for the osteomalacia seen in patients on long-term therapy with these two anticonvulsant drugs.515 Interestingly, phenobarbital induces glucuronyltransferase enzymes, thereby enhancing the conjugation of bilirubin with glucuronic acid. Phenobarbital has been used occasionally to treat hyperbilirubinemia in neonates.516

Putative Effect Of The Kd On Npy And Galanin Systems

Taken together, these data indicate that starvation conditions induce the expression of galanin and NPY. It stands to reason that these peptides would also be induced by the KD. A combination of the starvation-like phenotype, i.e., ketosis, and low glucose intake elicited by the KD would lead to decreased leptin and insulin. Low leptin and insulin levels would stimulate the activity of NPY-ergic neurons and increase NPY and galanin expression. Furthermore, because fat ingestion may enhance galanin expression, galanin expression would also be increased by chronic consumption of the high-fat KD.

Physiological Relevance of Inverse Agonists

A second receptor system with an endogenous inverse agonist is the family of mel-anocortin receptors (MCRs) 25 . To date, four MCR subtypes have been identified. The melanocortin receptor system represents the only example for which both an endogenous agonist (melanocortin, a-MSH) and an inverse agonist (agouti) have been identified. Melanocortin stimulates melanin pigment synthesis in skin melanophores through activation of MQ receptors (MQRs), resulting in a dark skin or hair color. The agouti protein acts as a competitive antagonist to prevent a-MSH from binding to the receptor and suppresses basal MCR activity, resulting in a yellow hair color. The receptor subtypes MC3R and MC4R, which are expressed in the brain, are involved in the development of obesity and cachexia. Agouti and agouti-related protein (AgRP) act as inverse agonists at these receptors 25 . AgRP and a-MSH are expressed by distinct neurons of the arcuate nucleus of the hypothalamus. Both groups of neurons sense...

Qualitative vs Quantitative Pharmacophore Models

Notably, the obtained quantitative models are somewhat different from qualitative ones, as produced by the Catalyst module HipHop 27 while the qualitative model seeks to find common features present in all models of the training set, the quantitative method looks primarily for those features that can explain the high affinity of the most active compounds, and which are not present in the lesser active ones. Often publications report the use of structurally closely related compounds for the generation of quantitative pharmaco-phore models. This may be largely because during optimization of initial lead structures, where this method is preferentially applied, medicinal chemists usually work on a distinct chemical class of compounds. A qualitative model based on highly similar compounds identifies all those features that were not changed (for whatever reason) as being equally important for the binding, and therefore often identifies also structurally quite similar compounds in a database...

Therapeutic Potential of 5HT2C Receptor Drugs for Reward Related Behavioral Problems

Because 5-HT2C receptors modulate reward-related behaviors, a logical question about the therapeutic potential of drugs like lorcaserin is whether this can be extended to the treatment of drug abuse. Several neurochemical systems, including DA, endogenous opioids, and cannabinoids, that are involved in drug abuse and dependence are also involved in the control of different aspects of feeding behavior (Kirkham 2009 Barbano and Cador 2007 Barbano et al. 2009). Similarly, the neuropeptides leptin and orexin that are involved in mediating aspects of feeding behavior also modulate reward-related behaviors (Borgland et al. 2006 Fulton et al. 2000). Thus, there is convergence and overlap of brain mechanisms and systems involved in reward-related behaviors relevant to obesity and substance abuse (Trinko et al. 2007 Volkow and Wise 2005). It is feasible then that a serotonergic drug that is effective in treating obesity may have potential in treating addiction.

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

The HPA axis is the primary neuroendocrine system mediating the stress response and includes the hormones and structures mediating the production of glucocorticoids. Corticotrophin-releasing hormone (CRH), also known as corticotrophin-releasing factor (CRF), is produced in the paraventricular nucleus of the hypothalamus. It acts on CRF1 and CRF2 receptors in the central nervous system and anterior pituitary (34). The CRF1 receptor mediates anxiety and depression behaviors and the stress response. The role of CRF2 is not known, but has been hypothesized to counter the actions of CRF1. Alternatively, it may be that CRF1 is activated by escapable stressors and CRF2 is activated by inescapable stressors. It is a major regulator of basal and stress-induced release of proopiomelanocortin (POMC) and POMC-derived peptides, such as adrenocorticotrophic hormone (ACTH) and beta-endorphin, from the anterior pituitary. ACTH acts on the adrenal cortex to promote synthesis and release of cortisol...

Coordination of GCMediated Control of the Neuroimmune Response and Energy Homeostasis Control

On the other hand, GC-induced biosynthesis of both 2-AG and AEA in the PVN is completely blocked by leptin (Malcher-Lopes et al., 2006), which is an anorexigenic cytokine-like peptide produced by the adipose tissue, functioning as a major peripheral signal informing the CNS about the current nutritional state (Ahima, 2000 Ahima and Osei, 2004 Ahima et al., 1996). Leptin was also shown to prevent fasting-induced hyperphagia by blocking fasting-induced biosynthesis of endocannabinoids in the hypothalamus (Di Marzo et al., 2001 Kirkham et al., 2002). There are evidences that leptin-promoted short-term suppression of appetite and meal termination involves the activation of preautonomic oxytocinergic PVN neurons (Blevins Leptin can also stimulate SAS outflow when injected i.c.v. however, the primary hypothalamic site for this action seems to be the ventromedial hypothalamus, not the PVN (Satoh et al., 1999). Leptin is released by adipose tissue in response to...

CYP Gene Variants Interacting with Vascular Homeostasis

Were significantly lower, which might result in reduced vascular protection 19 . Recently, a functionally deficient variant of CYP4A11 (T8590C) was associated with blood pressure control in humans 179 and with hypertension in the MONICA Augsburg Echocardiographic Substudy 180 . Additionally, a promoter polymorphism in CYP2E1, present in CYP2E1*1D increases CYP2E1 enzyme activity and ROS production and enhances its inducibility associated with obesity and ethanol intake 141 . Furthermore, CYP3A5, the only CYP3A enzyme in the kidney, which is absent in the majority of Caucasians, has been implicated in renal sodium reabsorption and blood pressure regulation via renal metabolism of cortisol and or aldosterone 150,165-169 . Interestingly, carriers of a wt allele showed higher insulin resistance than those homozygous for CYP3A5*3 (no enzyme activity) 170 .

Specificity of Drug Candidates and the Construction of In Vitro Specificity Panels

Ligands for NRs can be classified into naturally occurring ligands and synthetic ligands. The natural ligands (such as 17-0-estradiol (ER), testosterone (AR), progesterone (PR), cortisol (GR), and aldosterone (MR), all-trans retinoic acid (RAR), L-3,5,3'-L-triiodothyronine (T3) (TR), 9-cis-retinoic acid (RXR) and 1,25-dihydroxy vitamin D3) are all small and fairly rigid molecules with a high degree of hydropho-bicity. This overall hydrophobic nature facilitates diffusion across cell membranes. The importance of the NRs as medicinal targets has resulted in the generation of an enormous number of synthetic compounds that have advanced understanding of the NR ligand requirements.31 Agonist and antagonists of NRs are terms often used to describe ligands that either activate or repress transcription in transient transfection reporter gene assays however, these are inadequate for the description of NR ligands.

Effects of Upstream and Downstream Processes

The suppressors of SOCS system, which modulates certain cell surface receptors by inhibiting downstream signal transduction pathways and targeting receptors for degradation through the proteosome, may have effects upstream or downstream of the therapeutic target (see sect. Target-Mediated Elimination Pathways). Specific SOCS family proteins have been shown to regulate signaling by IFN-a, insulin, leptin, G-CSF, and somatotropin (31,32,39-41). Several Pgx studies have found significant associations between SOCS1 and SOCS3 genotypes or pretreatment mRNA levels and response to IFN-a treatment in chronic hepatitis C patients (35-38).

Control Of Npy And Galanin Expression By Nutritional Status

The circulating hormones leptin and insulin have inhibitory effects on the expression of orexigenic neuropeptides. Leptin is a satiety hormone that is secreted by fat cells and serves as a signal of energy stores. When energy stores are abundant, leptin levels are high. Leptin decreases food intake via two mechanisms. Leptin activates preprome-lanocortin (POMC) neurons in the ARC, which release a-melanocyte-stimulating hormone (a-MSH). a-MSH stimulates cells expressing melanocortin-4 receptors, leading to a decrease in food intake. Conversely, leptin inhibits NPY-containing neurons and decreases the hypothalamic expression of NPY and galanin. Furthermore, NPY expression is induced when leptin levels are low, e.g., during food deprivation and in leptin-deficient rodents, leading to an increase in food intake (4,11,16,17). bloodstream via the actions of glucagon. Insulin, like leptin, inhibits NPY-ergic neurons and suppresses the expression of NPY and galanin in the hypothalamus...

Changing the degree of unsaturation

The introduction of a double bond increases the rigidity of the structure. It may also introduce the complication of E and Z isomers, which could have quite different activities (see Table 1.1). The analogues produced by the introduction of unsaturated structures into a lead compound may exhibit different degrees of potency or different types of activities. For example, the potency of prednisone is about 30 times greater than that of its parent compound cortisol, which does not have a 1-2 C-C bond. The replacement of the S atom of the antipsychotic phenothiazine drugs by a -CH-CH- group gives the antidepressant dibenzazepine drugs, such as protriptyline. Cortisol Cortisol

Perspectives For Pharmacogenetic Research Into Eating Disorders And Obesity

The antidepressant drug Fluoxetine, a more selective serotonin reuptake inhibitor, is generally well tolerated and may be an effective treatment option for adolescents with bulimia nervosa. (Kotler et al., 2003). Treatment with fluoxetine in patients with bulimia nervosa improved outcome and decreased the likelihood of relapse. (Romano et al., 2002). Fluoxetine may also prevent relapse in AN. It dimishes associated symptoms of anorexia nervosa following adequate weight restoration (Kim, 2003). Thus, for the treatment response to fluoxetine, genes constituting the serotonin system may play a role. Since serotonin 2C receptors expressed on leptin-sensitive POMC cells mediate at least some of the effects of the reuptake inhibitor fenfluramine on eating behaviour, also the neuropeptidergic genes implicated in the leptin response, are candidate genes for the treatment responsiveness of this class of drugs. Genes influence susceptibility for obesity and eating disorders via traits within...

The Macrophage Theory Of Depression

Of all the endocrine changes that are reported to occur in stress and depression, Cortisol hypersecretion is the most frequently observed. Although hypercortisolaemia can arise as a consequence of an acute stressor, there is a qualitative difference between the circadian pattern of Cortisol secretion in the depressed patient and that observed following exposure to a stressful stimulus. Thus the nadir of the plasma Cortisol concentration occurs some 6 hours earlier in the depressed patient than in the stressed, non-depressed patient. The ACTH concentration is also elevated while the concentration of corticotorphin releasing factor (CRF) in the cerebrospinal fluid is raised in depressed patients (Linkowski, Mendlewicz, and Kerklofs, 1987 Nemeroff, Widerlov, and Bissette, 1984). As there is a close association between plasma glucocorticoids and immune function, it is often assumed that the immune changes are a direct consequence of the raised plasma, and brain concentrations of the...

Neuroendocrine Effects

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and ACTH. As a result of the decreased concentrations of pituitary trophic hormones, plasma concentrations of sex steroids and cortisol decline. Thyrotropin secretion is relatively unaffected.

Hypothalamicpituitaryadrenal Axis

The HPA axis transforms stressful stimuli into hormonal messages that enable the organism to adapt to environmental change and to maintain the body's homeostasis. Corticotropin-releasing hormone (CRH) is synthesized in the hypothalamus and is stimulated by stressors, which can be either physical (e.g., exercise, starvation) or psychological (e.g., perceived danger, stressful life events). The HPA axis is closely linked to the autonomic nervous system, and brain stem catecholamine systems can also activate CRH release (Herman et al. 1990 Plotsky 1987 Plotsky et al. 1989). CRH stimulates secretion of pituitary adrenocorticotropic hormone (ACTH), resulting in the secretion of glucocorticoids by the adrenal cortex in a feedforward cascade. Cortisol is the main glucocorticoid, and its secretion is tightly controlled by negative feedback effects of glucocorticoids at both pituitary and brain sites. These comprise very rapid real-time inhibition of the stress response that prevents...

Role of Pharmacotherapy

This is the most common psychiatric diagnosis in medically ill inpatients in acute care general hospitals referred for consultation, with rates ranging from 11.5 to 21.5 . Fabrega et al, at the University of Pittsburgh, observed that 2.3 of patients in a walk-in clinic had adjustment disorder only, while in those with other psychiatric or personality disorder comorbidity, the rate was 20 . Mezzich et al, from the same institution, observed that 29 of the patients in the adjustment disorder group had a positive response on indicators for suicide risk, whereas such indicators were seen in 9 of the normal (no illness) group. This emphasizes that a subthreshold diagnosis may be associated with serious symptomatology and mortality as an outcome. Obviously, suicidality is not subthreshold. Adjustment disorder patients with suicidality had lower platelet monoamine oxidase (MAO) activity, higher activity of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol...

Physiological Manipulations

Direct administration of naturally occurring neuropeptides, hormones, and cytokines has been used in animal models to identify physiological factors that induce behavioral symptoms of depression in humans. For example, chronic stress levels of cortisol systemically administered to squirrel monkeys impair prefrontal-dependent cognitive control of impulsive behavior (Lyons et al. 2000). Cortisol administered to healthy humans induces prefrontal-dependent cognitive impairments that resemble those that are caused in humans by prefrontal lesions (Lupien et al. 1999 A. H. Young et al. 1999). Humans with psychotic major depression consistently present with endogenous hypercortisolism (Nelson and Davis 1997), and patients with psychotic major depression are impaired on standardized tests of prefrontal cognitive functions (Schatzberg et al. 2000). Based on these findings, drugs that block cortisol at the receptor level are now being tested as novel treatments for psychotic major depression...

Inhibitors Of The Biosynthesis And Action Of Adrenocortical Steroids

Trilostane is a competitive inhibitor of the conversion of pregnenolone to progesterone, a reaction catalyzed by 3(3-hydroxysteroid dehydrogenase. All of these agents pose the common risk of precipitating acute adrenal insufficiency thus, they must be used in appropriate doses, and the status of the patient's HPA axis must be carefully monitored. AMINOGLUTETHIMIDE Aminoglutethimide (a-ethyl-p-aminophenyl-glutarimide cyta-dren) primarily inhibits CYP11A1, which catalyzes the initial step in the biosynthesis of all physiological steroids. As a result, the production of all classes of steroid hormones is impaired. Aminoglutethimide also inhibits CYP11B1 and CYP19 (aromatase), which converts androgens to estrogens. Aminoglutethimide has been used primarily to decrease hypersecretion of cortisol in patients with Cushing's syndrome secondary to autonomous adrenal tumors or ectopic production of ACTH. Dose-dependent GI and neurological side effects are relatively common, as...

Effect of Meta Chlorophenylpiperazine a 5HT2C Agonist as a Challenge Agent in Schizophrenia

There are conflicting data on the effect of the acute administration of mCPP, a mixed 5-HT2A 2C agonist, to patients with schizophrenia, with one study reporting a decrease in psychotic symptoms (Kahn et al. 1992) three others, a mild exacerbation of positive symptoms (Iqbal et al. 1991 Krystal et al. 1993) and two, no significant effect (Maes and Meltzer 1996 Koreen et al. 1997). The reasons for these discrepancies are unclear. It is not related to route of administration, severity of symptoms, or gender. Maes and Meltzer (1996) also reported no differences in the mCPP-induced prolactin, cortisol, or temperature responses in patients with schizophrenia who were neuroleptic free at the time of study. Clozapine has been reported to antagonize the cortisol response to mCPP in patients with schizophrenia, consistent with its 5-HT2C antagonist properties (Kahn et al. 1994 Owen et al. 1993). Two studies reported no difference in the cortisol or adrenocorticotropic hormone (ACTH) response...

Implications of Estrogens in Human Breast Carcinogenesis

17f-Estradiol and estrone, which are continuously interconverted by 17ff-estradiol hydroxysteroid dehydrogenase (or 17f-oxidoreductase), are the two major endogenous estrogens (Fig. 10). They are generally metabolized via two major pathways hydroxylation at C16a position and at the C2 or C4 positions

Classic Neurotransmitters and the Monoamine Hypothesis of Depression

NE neurons in the locus coeruleus (LC) project to almost all major brain regions and serve an important role in regulating and focusing additional and other responses to external stimuli (127, 128). Not surprisingly, NE systems are involved in responses to stress since there are multiple interactions between the HPA axis and NE. For instance, under experimental conditions, CRF secretion increases LC neuronal firing, resulting in enhanced NE release. NE release stimulates CRF secretion in the paraventricular nucleus (PVN) which leads to ACTH secretion. Increased ACTH leads to increased cortisol which provides a negative feedback to decrease CRF and NE in the PVN.

Effect of HPA Axis on the Reproductive Axis

While early studies used peripheral administration of high doses of CRH, subsequent studies demonstrated that intracerebrovascular administration of CRH demonstrated much greater potency and confirmed a central site of action of the inhibition, pointing to direct inhibition of GnRH by CRH (Gambacciani et al. 1986 Nikolarakis et al. 1986a, 1986b Olster and Ferin 1987 Petraglia et al. 1987). However, the peripheral administration of CRH also demonstrated an opioid-mediated inhibition by CRH that could be abolished by dexamethasone pretreatment, suggesting a role for pituitary-derived opioids, most probably -endorphin from anterior pituitary corticotropes. Anatomical studies demonstrate that CRH neurons synapse with GnRH neurons (MacLusky et al. 1988) in vitro studies demonstrate that CRH can function as a secretagogue for ( -endorphin secretion from the arcuate -endorphin system (Nikolarakis et al. 1986a). Studies in primates by the Knobil laboratory (Williams et al. 1990) recording...

Stress Obesity and Metabolic Syndrome

So, can perceived stress and its biological correlate lead to metabolic disturbance The answer would seem to be yes, in that, stress be it social or work-related leads to an immediate activation of the sympatho-adrenal network which leads to an outpouring of norepinephrine and cortisol which in healthy non-obese individuals results in tachycardia, a reflex vasodilation and the disposal of glucose while the opposite metabolic effects are seen in obesity 54 . The origin of the stress can be work-related or otherwise, as suggested in a study by Chandola et al. 55 who found that such stress was associated with higher cortisol levels in the morning and was directly related to the future development of IHD. Healthy individuals respond to stress in a unitary fashion with the activation, as mentioned already, of the sympatho-adrenal system and the HPA axis resulting in an increase of cortisol and epinephrine. One immediate consequence of this is an increase in resting heart rate and a...

Principles of Negative Feedback Illustrated by the HPA System

Glucocorticoids exert their inhibitory action both on the brain and the pituitary gland (Figures 5 and 6). The paraventricular nuclei (PVN) of the hypothalamus contain the final common pathway neurons that mediate neural control of pituitary ACTH synthesis and release. The PVN receive stimulatory and inhibitory neural inputs, and an important projection from the suprachiasmatic nuclei (SCN), the key circadian oscillator in brain, and PVN drive is mediated by stress neurohormones released into hypophysial portal vessel blood. ACTH is released into the systemic circulation and stimulates adrenal corticosteroid synthesis and release. For negative feedback, the glucocorticoids (Cortisol and corticosterone) are the most important of the adrenal steroids. The release of ACTH is pulsatile in man and is rapidly cleared from the blood both by metabolic degradation and distribution into several body compartments. The glucocorticoids are rapidly bound by albumin and a specific corticosteroid...

Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

Dynamic challenges of the HPA axis have also provided conflicting results probably for the same reasons quoted above. That aside, the dexamethasone suppression test (dexamethasone normally inhibits the secretion of ACTH and cortisol) is abnormal in nearly 50 of subjects with schizophrenia 12 though this is not a very sensitive test as such findings have also been shown in post-traumatic stress disorder 13 and Alzheimer's disease 14 . Delta-9-tetrahydro-cannbinol, an active cannabis ingredient, when given to subjects with schizophrenia results in high cortisol levels and can cause a heightening of positive, negative and cognitive symptoms 15 . ACTH increases are greater in patients than matched controls when metabolic stress is induced centrally by 2-deoxy-D-glucose (2-DG) 5 while some investigators have shown that CRH-stimulated ACTH and cortisol are normal however, pretreatment with dexamethasone leads to increased cortisol secretion in patients with established schizophrenia 16 ....

HPA Axis in Depression and Anxiety Disorders Depression

Overactivity of the HPA axis as manifested by an increase in cortisol secretion is now a well-established phenomenon in depression (Carroll et al. 1976 Sachar et al. 1973). The first studies (Sachar et al. 1973) showed that up to 50 of depressed patients have higher mean plasma cortisol concentrations and an increased number and duration of cortisol secretory episodes, suggesting increased cortisol secretory activity. Numerous studies have subsequently validated these findings (Carroll et al. 1976 Halbreich et al. 1985 Krishnan et al. 1990a Pfohl et al. 1985 Rubin et al. 1987). As many as two-thirds of endogenously depressed patients fail to suppress cortisol, or show an early escape of Cortisol, following overnight administration of 1 mg of dexamethasone (using a Cortisol cutoff of 5 L g dL to define escape) (Carroll et al. 1981). While nonsuppression of Cortisol in response to dexamethasone is strongly associated with endogenous depression, this finding is less robust in outpatients...

Estradiol and Estrone

Estradiol And Estrone

The mammalian estrogens E2 and estrone (E1), which are interconvertible in the cell by the enzyme 17 -hydroxysteroid dehydrogenase, are human and animal carcinogens 1 . An established animal model is the male Syrian golden hamster, in which carcinogenic estrogens lead to a 100 incidence of kidney tumors. The observation that several potent steroidal estrogens, e.g., 17a-ethinyl-E2 and 2-fluoro-E2, are virtually noncarcinogenic for the hamster kidney 2 is not consistent with the paradigm that the stimulation of cell proliferation and the eventual accumulation of spontaneous mutations 3 is the cause of hormonal cancer. This was one of the reasons that prompted several laboratories to study other mechanisms, in particular the role of genotoxic metabolites. Several recent reviews have detailed the current state of knowledge in this field 4-10 . As depicted in Fig. 2, the major pathways in the oxidative metabolism of E2 and E1 comprise hydroxylation at C-2, C-4, and C-16. The catechol es-

Steroid Hormonal Factors in Populations with Different Risk for Prostate Cancer

The human HSD3B2 gene, which is located on chromosome 1p13 and encodes for type II 3 -hydroxysteroid dehydrogenase (an enzyme that catabolizes DHT and is expressed in the adrenals and testes), contains several complex di-nucleotide polymorphisms 152 .Devgan et al. 154 reported that the frequency of HSD3B2 alleles differs among ethnic groups. African American men are unique in one minor allele, and the most common allele is more frequent in European Americans than in either African Americans or Asian men. The second most common allele is more frequent in African Americans than in either Asians and European men. However, the functional significance of these HSD3B2 gene polymorphisms is unknown.

Glucocorticoid Resistance In Depression

Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry. Patients with major depression exhibit elevated Cortisol concentrations in plasma, urine, and cerebrospinal fluid (csf) an enlargement of both the pituitary and adrenal glands, and an exaggerated Cortisol response to ACTH (Owens & Nemeroff, 1993 Holsboer & Barden, 1996). The etiology of these HPA axis alterations is believed to be a function of hypersecretion of CRH. CRH is a key regulatory peptide in HPA axis regulation and has a multitude of behavioral effects in animals which are similar to those seen in patients suffering from depression including alterations in activity, appetite, and sleep (Owens & Nemeroff, 1993). Moreover, patients with depression have been found to exhibit increased concentrations of CRH in the csf, increased mRNA in the paraventricular nucleus of the hypothalamus, and a blunted ACTH...

The Sterols And Steroid Hormones

Whereas cholesterol and the bile acids are produced in gram quantities in the body, the hormonal steroids are found in milligram quantities. The steroidal cortical hormones, e.g. cortisol 5.57, are produced by the adrenal cortex and are involved in the regulation of carbohydrate, lipid and protein metabolism (glucocorticoid effects) and in the regulation of electrolyte balance (mineral corticoid effects). They also have immunosuppressive activity.

Treatment Of Alcoholdependence

An alternative mechanism could implicate the modification of stress coping capacity, as some alcohol-dependent patients sustain a relative deficiency in endogenous opioids after experiencing a stressful life event (Volpicelli, 1987 Volpicelli et al., 1990 Kreek, 1996). Fuerthermore, cortisol stimulation in early abstinent alcoholics showed a blunted response after psychosocial stress (Lovallo et al., 2000). A successful response to stress plays an important role in maintaining health and well-being. In recently detoxified alcoholics, the HPA system is indeed dysregulated with non-suppression of cortisol after dexamethasone administration. Corticotropin releasing factor (CRF) neurons, within the paraventricular nucleus of the hypothalamus, initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al., 1998) and express mu-opioid receptors. CRF neurons are thus modulated by inhibitory tone imposed by P-endorphin neurons originating in the arcuate nucleus (Wand et...

Metabolism And Inactivation

Insulin-induced hypoglycaemia is a strong stimulator of pituitary adrenocorticotrophin (ACTH) secretion (Caraty et al., 1990). After the injection of a low (0.2 IU kg1) or high (2 IU kg*1) dose of insulin, ACTH and Cortisol levels in peripheral plasma increased in a dose-related manner. When the hypoglycaemia is moderate, corticotrophin-releasing factor (CRF) is the main factor triggering ACTH release, and the increased arginine-vasopressin (AVP) secretion potentiates the stimulatory effect of CRF. When hypoglycaemia is deeper, AVP secretion becomes predominant and may by itself stimulate ACTH release (Caraty et al., 1990).

Muscarinic M2 Receptors

Muscarinic M2 receptors may play a role in adult depressive disorders. Serum cortisol levels are elevated in major depressive disorders, notably in adult women (Cannon et al. 2010). Females possessing a thymidine at nucleotide 1890 in the 3' untranslated region of the human M2 receptor gene have an elevated predisposition for major depression. Subsequent work has shown that six single nucleotide polymorphisms (SNPs) have been shown to decrease muscarinic M2 receptor binding present in the CHRM2 gene associated with bipolar depression. In mice, muscarinic M2 receptors mediate agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis, as animals deficient in this subtype do not show enhanced release of serum corticosterone in response to muscarinic agonists (Hemrich-Luecke et al. 2002). Moreover, centrally active muscarinic agonists stimulate the hypothalamic-pituitary-adrenocortical axis via the release of cortico-trophin-releasing hormone. However, it is unclear...

Preclinical Studies of PPARy Agonists in Animal Models of AD

APP levels as well as BACE expression, augmenting Aft formation as well as accelerating the formation of neurofibrillary tangles 154 . AD patients also exhibit elevated levels of plasma cortisol. Furthermore, a study carried out in macaques demonstrated that year-long administration of cortisol was correlated with a reduction in IDE protein and mRNA levels in the frontal cortex and hippocampus and a selective increase in the levels of Aft42 levels without affecting overall plaque burden suggesting a correlation between high gluco-corticoid levels and IDE and AD pathophysiology 155 . The hypothesis that rosiglitazone's actions in the Tg2576 mice arise from its effects on peripheral glucocorticoid levels is compelling. PPARy agonists are not reported to have analogous effects on glucocorticoids in humans and thus the relevance of this mechanism to AD therapy is unclear.

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