Lose Weight By Controlling The Fat Storage Hormone

Trouble Spot Nutrition

Created by Janet Hradil, Trouble Spot Nutrition is a 3 Phase Hormonal Solution That Melts Away Trouble Spot Fat In Less Than 15 Minutes A Day. Leptin, cortisol, and testosterone all have an influence on our weight issues, but not many of us know it. Janet Hradil has created Trouble Spot Nutrition with the intent of teaching people how their hormones affect their weight loss efforts, and how nutrition can easily correct hormone issues and help fight fat faster than ever before. In each of your fat cells, there is an enzyme, 11 beta-hydroxysteroid dehydrogenase-1 (Hsd), that takes inactive cortisone (a hormone) and turns it into cortisol, a fat storing compound. If you have high amounts of Hsd, you will have high amounts of fat storage. While Hsd is genetically determined, you can use nutrition to reduce levels and stop the unwanted fat storage, even on your trouble spots. Read more here...

Trouble Spot Nutrition Summary

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Leptin and Other Hormones

The most promising antiobesity treatment once involved the anti-fat hormone, leptin its discovery led to a surge of obesity drug research. Leptin, discovered in 1994, seemed promising because it is produced by fat cells and was the first antiobesity hormone that surfaced. The leptin hormone receptor was discovered in 1997 when a mutant strain of extremely obese mice (lacking the gene to make leptin) were able to shed their weight when given leptin. With injections of leptin, the mice's appetite decreased while their metabolic rates increased. Although researchers wondered whether all obese people would lose weight on leptin, this did not occur. It turns out that, like the mutant obese mice, there are only a few rare cases known of human obesity caused by leptin deficiency. Most people seem to become obese by eating too much and being too sedentary. The leptin discovery should provide a successful treatment for rare cases of obesity in leptin-deficient individuals who, in the past,...

Other Effects of Cortisol

Cortisol Blocks the Inflammatory Response to Allergic Reactions. The basic allergic reaction between antigen and antibody is not affected by cortisol, and even some of the secondary effects of the allergic reaction still occur. However, because the inflammatory response is responsible for many of the serious and sometimes lethal effects of allergic reactions, administration of cortisol, followed by its effect in reducing inflammation and the release of inflammatory products, can be lifesaving. For instance, cortisol effectively prevents shock or death in anaphylaxis, which otherwise kills many people, as explained in Chapter 34. Cortisol decreases the number of eosinophils and lymphocytes in the blood this effect begins within a few minutes after the injection of cortisol and becomes marked within a few hours. Indeed, a finding of lym-phocytopenia or eosinopenia is an important diagnostic criterion for overproduction of cortisol by the adrenal gland. Likewise, the administration of...

Cellular Mechanism of Cortisol Action

Cortisol, like other steroid hormones, exerts its effects by first interacting with intracellular receptors in target cells. Because cortisol is lipid soluble, it can easily diffuse through the cell membrane. Once inside the cell, cortisol binds with its protein receptor in the cytoplasm, and the hormone-receptor complex then interacts with specific regulatory DNA sequences, called glucocorti-coid response elements, to induce or repress gene transcription. Other proteins in the cell, called transcription factors, are also necessary for the hormone-receptor complex to interact appropriately with the glucocorti-coid response elements. Glucocorticoids increase or decrease transcription of many genes to alter synthesis of mRNA for the proteins that mediate their multiple physiologic effects. Thus, most of the metabolic effects of cortisol are not

Regulation of Cortisol Secretion by Adrenocorticotropic Hormone from the Pituitary Gland

Adrenocorticotropic Hormone

Unlike aldosterone secretion by the zona glomerulosa, which is controlled mainly by potassium and angiotensin acting directly on the adrenocortical cells, almost no stimuli have direct control effects on the adrenal cells that secrete cortisol. Instead, secretion of cortisol is controlled almost entirely by ACTH secreted by the anterior pituitary gland. This hormone, also called corticotropin or adrenocorticotropin, also enhances the production of adrenal androgens. The most important of all the ACTH-stimulated steps for controlling adrenocortical secretion is activation of the enzyme protein kinase A, which causes initial conversion of cholesterol to pregnenolone. This initial conversion is the rate-limiting step for all the adrenocortical hormones, which explains why ACTH normally is necessary for any adrenocortical hormones to be formed. Long-term stimulation of the adrenal cortex by ACTH not only increases secretory activity but also causes...

Effects of Cortisol on Protein Metabolism

One of the principal effects of cortisol on the metabolic systems of the body is reduction of the protein stores in essentially all body cells except those of the liver. This is caused by both decreased protein synthesis and increased catabolism of protein already in the cells. Both these effects may result from decreased amino acid transport into extra-hepatic tissues, as discussed later this probably is not the major cause, because cortisol also depresses the formation of RNA and subsequent protein synthesis in many extrahepatic tissues, especially in muscle and lymphoid tissue. In the presence of great excesses of cortisol, the muscles can become so weak that the person cannot rise from the squatting position. And the immunity functions of the lymphoid tissue can be decreased to a small fraction of normal. Cortisol Increases Liver and Plasma Proteins. Coinciden-tally with the reduced proteins elsewhere in the body, the liver proteins become enhanced....

How Plasma Proteins Slows Elimination Of Cortisol

Glucocorticoid and mineralocorticoid activities of the steroids are relative to Cortisol, with Cortisol being 1.0. Cortisol (very slight mineralocorticoid activity, but large quantity secreted) Cortisol (very potent, accounts for about 95 per cent of all glucocorticoid activity) Corticosterone (provides about 4 per cent of total glucocorticoid activity, but much less potent than cortisol) Cortisone (synthetic, almost as potent as cortisol) Prednisone (synthetic, four times as potent as cortisol) Methylprednisone (synthetic, five times as potent as cortisol) Dexamethasone (synthetic, 30 times as potent as cortisol) It is clear from this list that some of these hormones have both glucocorticoid and mineralocorticoid activities. It is especially significant that cortisol has a small amount of mineralocorticoid activity, because some syndromes of excess cortisol secretion can cause significant mineralocorticoid effects, along with its much more potent glucocorticoid effects. Approximately...

Effects of Cortisol on Fat Metabolism

In much the same manner that cortisol promotes amino acid mobilization from muscle, it promotes mobilization of fatty acids from adipose tissue. This increases the concentration of free fatty acids in the plasma, which also increases their utilization for energy. Cortisol also seems to have a direct effect to enhance the oxidation of fatty acids in the cells. The mechanism by which cortisol promotes fatty acid mobilization is not completely understood. However, part of the effect probably results from diminished transport of glucose into the fat cells. Recall that a-glycerophosphate, which is derived from glucose, is required for both deposition and maintenance of triglycerides in these cells, and in its absence the fat cells begin to release fatty acids. The increased mobilization of fats by cortisol, combined with increased oxidation of fatty acids in the cells, helps shift the metabolic systems of the cells from utilization of glucose for energy to...

Effects of Cortisol on Carbohydrate Metabolism

By far the best-known metabolic effect of cortisol and other glucocorticoids on metabolism is their ability to stimulate gluconeo-genesis (formation of carbohydrate from proteins and some other substances) by the liver, often increasing the rate of gluconeogenesis as much as 6- to 10-fold. This results mainly from two effects of cortisol. 1. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells. This results from the effect of the glucocorticoids to activate DNA transcription in the liver cell nuclei in the same way that aldosterone functions in the renal tubular cells, with formation of messenger RNAs that in turn lead to the array of enzymes required for gluconeogenesis. 2. Cortisol causes mobilization of amino acids from the extrahepatic tissues mainly from muscle. As a result, more amino acids become available in the plasma to enter into the gluconeogenesis process of the liver and thereby to promote the...

The Leptin Receptor

The leptin receptor (ObR) is a member of the cytokine receptor superfamily and is coded for by the diabetes gene db7 9. Mice with dbjdb mutation have the same obese phenotype as ob ob mice. The db gene encodes at least five alternatively spliced forms of the receptor ObR-a-e in mice and four in humans9-. The ObR b is the full-length receptor and is essential for the weight-reducing effects of leptin. ObR a is expressed in the choroid plexus and other tissues but its function is unknown. It has some weak signalling activity. The functions of the ObR-c, -d and -e forms are also unknown but may be involved in transport or form heterodimers with the other forms'.

Leptin

Leptin is increased in OSA, even when obesity is taken into account 17 . This suggests that OSA leads to leptin resistance. The increase in leptin in OSA may be due to increased sympathetic activity. Leptin reduces food intake, increases activity and energy expenditure and is also a respiratory stimulant, increasing the ventilatory response to carbon dioxide. Leptin resistance may contribute to the obesity hypoventilation syndrome. Treatment with CPAP reduces the leptin level in OSA independently of any effect on the body mass index.

Fat Deposits

Large quantities of fat are stored in two major tissues of the body, the adipose tissue and the liver. The adipose tissue is usually called fat deposits, or simply tissue fat. Fat Cells (Adipocytes). The fat cells (adipocytes) of adipose tissue are modified fibroblasts that store almost pure triglycerides in quantities as great as 80 to 95 per cent of the entire cell volume. Triglycerides inside the fat cells are generally in a liquid form. When the tissues are exposed to prolonged cold, the fatty acid chains of the cell triglycerides, over a period of weeks, become either shorter or more unsaturated to decrease their melting point, thereby always allowing the fat to remain in a liquid state. This is particularly important, because only liquid fat can be hydrolyzed and transported from the cells. Fat cells can synthesize very small amounts of fatty acids and triglycerides from carbohydrates this function supplements the synthesis of fat in the liver, as discussed later in the chapter....

Diencephalic Dysfunction

Disorders of the diencephalon may affect consciousness either directly, by interfering with reticular system function, or indirectly, by producing endocrine disorders. These conditions may develop slowly, as with anterior pituitary syndromes resulting in hypothyroidism or cortisol deficiency, or rapidly, as with osmoregulatory disorders. The lesions producing these problems may also affect the cerebral cortex, as in the case of neoplasms, and produce seizures or other focal neurological disorders. Patients with structural diencephalic lesions may have toxic downward eye deviation, small pupils, decorticate posturing, and Cheyne-Stokes respirations as an archetype, although varying combinations of signs may appear.

Diagnosing Thyroid Disease

Besides forming proteins, some amino acids are used to form hormones, such as the amino acid tyrosine, which forms thyroid hormones when combined with iodine. The thyroid hormones, thyroxine and triiodothyronine, are members of the steroid hormone superfamily, which also includes cortisol, estrogen, progesterone, androgen, aldosterone, and vitamin D. All of these different hormones stick to special proteins in the nucleus (center part) of the cell called nuclear receptor proteins, which then stick to particular parts of different genes to do their own particular jobs. (See Chapter 1.) Proper use of laboratory tests ensures that hormones are doing their jobs.

Secondary Hypothyroidism Pituitary Problems

Often, tumors can recur, requiring external beam radiation therapy to prevent further enlargement. Rarely, some pituitary tumors make a hormone known as ACTH, causing Cushing's disease in which high levels of steroids (cortisol) are made. This dangerous condition is also treated by a transsphenoidal hypophysectomy, possibly resulting in hypothyroidism from pituitary damage. Many years ago, before improved obstetrical care, excessive loss of blood during childbirth could cause a drop in blood pressure that caused part of the pituitary to die and sometimes bleed, a condition known as Sheehan's syndrome. This can still happen to anyone with an unsuspected thyroid tumor who has a rapid drop in his or her blood pressure, resulting in destruction of the remaining pituitary, called pituitary apoplexy.

Stem Cells in Culture

Directed differentiation of adult stem cells has confirmed previous in vivo studies, which concluded that adult stem cells have less plasticity than ES cells. When stem cells from an adult mouse brain are placed in culture, they differentiate into different kinds of neural tissue but not the variety of cell types that are produced by ES cells. Likewise, adult stem cells from the bone marrow differentiate, in vitro, into blood cells, neurons, and fat cells, but not glandular tissue (see table on page 13). Moreover, scientists have less control over the differentiation process of adult stem cells than that of ES cells. Adult bone marrow stem cells differentiate spontaneously when placed in culture, and there is no way to stop them. Consequently, it is very difficult to maintain a continuous culture of these cells. So far, only mouse ES cells are able to proliferate in vitro for an indefinite period of time while retaining an embryonic phenotype.

Other Defense Factors In Milk Acting In The Infants

The presence of leptin in the milk43 may be of significance for the infant's host defense since leptin has the structure and several functions of a cytokine44,45.It stimulates haematopoeitic and lymphoid cells, especially TH1 cells which produce IFN-y it enhances phagocytosis and may upregulate inflammatory cytokines45 However, the role of milk leptin for the offspring has not yet been investigated, when it comes to its possible role for the immune system.

Neuroendocrine Responses to Stress

The hypothalamic-pituitary-adrenal (HPA) axis is one of the most widely studied of the stress responsive systems. This cascade begins with the release of CRH from the parvocellular neurons of the paraventricular nucleus of the hypothalamus into the external zone of the median eminence. From here CRH is carried through the portal blood system to the anterior lobe of the pituitary gland, where it acts as a secretagogue for adrenocorticotrophic hormone (ACTH). ACTH is then released into the systemic circulation and carried through the blood to the adrenal cortex, where it stimulates cells in the zona fasciculata to produce and release glucocorticoids. The glucocorticoid released in response to stress in the rat is corticosterone (CORT), while the human adrenal cortex secretes cortisol. Since corticosterone and cortisol vary only slightly in their chemical structure, both are classified as glucocorticoid hormones and bind to the same receptors in the body with comparable affinity. It is...

Entrainment Effect Of Lightdark Alternation

In about the middle of the 20th century it was demonstrated that the artificial administration of light stimulus on biological systems was able to induce a phase shift on circadian rhythm (3). The direction and the intensity of the shift changed according to when the stimulus was provided within the 24-hour day. The mathematical relationship between the time of light administration and the shift in the circadian system is graphically synthesized by the so-called phase-response curve (PRC) (4). The PRC shows that when the light stimulus is presented during the early subjective night it provokes a phase-delay shift, while the same stimulus presented in the late subjective night advances the circadian rhythm. The light effect during the subjective day is markedly reduced in some animals and, even abolished in others, during a time of the day known as the ''dead zone'' (5). Dark stimulus during the day usually has no effect. Until recently, several studies demonstrated that the...

Shared Underlying Pathophysiology Between Schizophrenia and Substance Abuse

Stress is important to the etiology of schizophrenia as well as craving for abused substances. Studies examining cumulative non-illness-related stressors have reported increased number of stressors a few weeks or months prior to the onset of relapse in schizophrenia, as well as in other psychiatric disorders (73-75). However, Norman and Malla (73) reported that the number of stressful life events in schizophrenia within the defined study period was not different from that in other psychiatric patients. Several clinical and preclinical studies suggest enhanced sensitivity to stress in schizophrenia. For example, patients with schizophrenia have been reported to have enhanced plasma homovanillic acid (HVA) (76), the major metabolite of DA, and greater adrenocorticotropine hormone (ACTH) (77) responses following metabolic stress compared to normal controls. Furthermore, various studies indicate abnormal regulation of the hypothalomic-pituitary-adrenal (HPA) axis in schizophrenia....

Metabolic and endocrine effects

A rise in Cortisol secretion early in the night, as is seen in depression and with ageing. There is a reduction in prolactin secretion and a loss of the circadian rhythm and quantity secreted of TSH. Sleep fragmentation reduces growth hormone secretion during the initial NREM sleep cycle, although there is some compensatory increase in secretion during wakefulness. This effect on growth hormone and the autonomic abnormalities both reduce lipolysis. The peak level of leptin, which is produced by fat cells, is normally seen at around 9.00 pm. In sleep deprivation less leptin is secreted. There is a smaller diurnal amplitude in its secretion, particularly in those who are obese and have a high initial leptin level. The findings are similar to those seen in the elderly. Ghrelin, released by the stomach, has opposite effects to leptin, and its secretion increases by around 25 in sleep deprivation. The lack of leptin and increase in ghrelin reduce the sensation of satiety and increase...

Hormonal Influences on Homeostatic Mechanisms

Insulin is secreted in response to increased levels of blood glucose. This may occur after a meal or if glucagon is released and circulating glucose increases. Increased insulin levels cause glucose to enter cells more quickly where it is either used for fuel or, in the case of fat cells, is converted to triglycerides and stored. Blood glucose levels then drop. Data support the contention that hunger and eating are initiated when nutrient levels, especially glucose levels, decrease in the blood. Thus a high insulin level could lead to hunger because it decreases blood glucose. Furthermore, insulin levels can be influenced by the hypothalamus, and disruption of this control by hypothalamic lesions may explain some of the effects of such lesions on eating behavior and body weight.

Gender Specific Behavior

Although conducted before the discovery of MIS, an early experiment by Phoenix, Goy, Gerall, and Young serves to distinguish the roles of these two hormones and demonstrates the importance of testosterone for masculization of adult behavior. Fetuses of both sexes are exposed to high estrogen levels from the mother's circulation. Thus the primary secretion of the fetal ovaries is reinforced by estrogen from the mother. Phoenix and colleagues wondered what would happen if female fetuses were exposed to higher than normal levels of testosterone. To answer this question, they

Circadian Dysregulation

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most reproducible biomarkers of major depressive disorder (reviewed in Holsboer, 2000). Increases in urinary cortisol production, levels of corticotropin-releasing hormone (CRH) in spinal fluid (Nemeroff, 1996), and a general disturbance in the normal pattern of cortisol secretion have been identified (Carroll et al., 1981). Blunted suppression of morning cortisol levels following oral dexam-ethasone administration, the so-called dexamethasone suppression test (DST), was previously considered a specific marker of depressive illness. It is now recognized as an abnormality in only some subsets of depressed patients, notably psychotic depressives. Also reported is blunted adrenocorticotrophic hormone (ACTH) response to exogenous CRH. More sensitive to detect HPA dysregulation is the combined use of the DST and the CRH stimulation test. In the setting of an abnormal HPA axis test, clinical...

Parental History of Hypertension

Studies comparing neuroendocrine responses to stress between offspring of hypertensive and normotensive parents also provide information regarding the role of the sympathetic nervous system in driving the observed cardiovascular response differences. In particular, if group differences in measures of epinephrine, norepinephrine, or cortisol were evident, greater sympathetic involvement could be presumed. Although increased levels of resting plasma norepinephrine (Horikoshi et al., 1985) and norepinephrine response to exercise were reported among individuals with hypertensive parents (Nielsen, Gram, and Pedersen, 1989), no differences in epinephrine between offspring of hypertensive and normotensive parents were reported. Other studies, however, have failed to find any differences in either norepi-nephrine or epinephrine levels or responses to mental and physical stressors among groups of offspring of hypertensive and normotensive persons (Manuck et al., 1996 Perini et al., 1990)....

Clinical features

There is a tendency towards an advanced sleep phase syndrome in depression (Fig. 7.3) which may contribute to early morning awakening 12 . In contrast, depression in the seasonal affective disorder causes excessive daytime sleepiness and a delayed sleep phase syndrome. Changes in circadian rhythms such as cortisol secretion are common in depression. Melatonin secretion is reduced in depression, possibly because of reduced 5HT and noradrenaline stimulation of the pineal gland. The amplitude of the diurnal temperature rhythm is lessened and core body temperature at night is higher than in normal subjects. The reduction in REM sleep latency correlates with both of these abnormalities.

Mania and manic depression bipolar disorder

Mania often leads to a feeling of being refreshed after only 3-4 h of sleep at night. It may even prevent sleep for several days, but the subject then becomes exhausted. The total sleep time is shortened, sleep latency is prolonged, there is a short REM sleep latency, the duration of stages 3 and 4 NREM sleep is often normal, but there can be a gross alteration in the sleep architecture. Abnormalities of circadian rhythms include changes in the diurnal cortisol secretion pattern.

Fatal familial insomnia

This condition is equally common in males and females. It is usually familial but occasionally sporadic, and usually appears between the ages of 40 and 70 years. Progressively worsening insomnia is associated with vivid dreams and motor activity similar to that of the REM sleep behaviour disorder. The fall in total sleep time is associated with disintegration of the sleep structure with no discernible NREM or REM sleep. The normal 24-h rest-activity cycle is lost and the circadian cortisol rhythm disappears. Autonomic and motor abnormalities appear, but cognitive function is retained until stupor and eventually coma develop shortly before death. This usually occurs 6-24 months after the onset of the condition.

Utilization and Validation of Ground and Animal Models

When ground and flight studies have been compared, the results have sometimes been surprising. For example, a flight study on the Life and Microgravity Spacelab shuttle mission by Wronski et al. (1998) attempted to address the effects of glucocorticoids on rat bones during spaceflight, since there was ample ground-based data to suggest that glucocorticoids had a major role in bone loss. No effect of spaceflight or of cortisol on bone growth was found. Analysis of this unexpected finding showed that changes in bone in rats induced by spaceflight were influenced by (1) the way the animals were housed, (2) the age of the animal, (3) the particular strain (genetic background) of the rat used in the study, and (4) flight duration. Group housing inhibited bone formation, whereas single housing did not. Instead of being simple, the rat model turns out to be complex

HT Precursor Challenge

5-Hydroxytryptophan (5-HTP) is the immediate precursor of 5-HT. Parenteral administration results in unacceptable side-effects so it is generally given orally and, probably because of this, hormone responses tend to be unreliable. An interesting difference from TRP challenge is the stimulation of cortisol secretion. Animal studies suggest 5-HT2 receptor-mediation of hormonal responses.21 In humans the GH response is antagonized by cyproheptidine, a more potent 5-HT2 than 5-HT1 receptor antagonist22 while the cortisol response is antagonized by ritanserin in one study23 but not another.24 Pindolol lacks effect on the cortisol response,25 but PRL stimulation appears to be antagonized by both ritanserin23 and pindolol.25 Therefore the mediation of 5-HTP-induced hormone responses in humans are not entirely certain although the involvement of 5-HT2 receptors seems most ACTH cortisol

HT Reuptake Inhibitor Releaser Challenge

Receptors.28 Administration to humans stimulates PRL and ACTH cortisol secretion. However, the widely held belief that hormonal responses are due to its 5-HT releasing action is difficult to reconcile with the persistence (sometimes increase) of responses after administration of drugs which block 5-HT reuptake, such as clomipramine, imipramine, amitriptyline, fluoxetine and fluvoxamine.29-32 Hormonal responses to fenfluramine may therefore be due to either 5-HT release independent of active 5-HT reuptake or due to direct postsynaptic receptor stimulation. Whatever the precise mechanism, antagonist studies suggest that the PRL response to fenfluramine is mediated by postsynaptic 5-HT2 receptors as they are antagonized by the 5-HT2A 2C receptor antagonists, ritanserin33 and amesergide,34 but not by pindolol35 or the 5-HT3 antagonist, ondansetron.36 The cortisol response to fenfluramine tends to be less robust it is often not reported and the 5-HT receptors involved have been less well...

Negative Affect Hypothesis

Despite the potential importance of depression for predicting essential hypertension, the literature examining the relation between depression and acute cardiovascular responses to stress is not substantial. Perhaps it may go without saying that because depression is typically thought to be associated with a dampened rather than an accelerated sympathetic nervous system response, fewer investigations of this hypothesis have been conducted. However, on the assumption that both depression and cardiovascular response to stress involve autonomic nervous system functioning, a few studies have examined this potentially important relation (Delehanty, Dimsdale, and Mills, 1991 Light, Kothandapani, and Allen, 1998). Although both studies found very limited support for the relation between depression and blood pressure response to stress, clear evidence was uncovered for the relation between depression and increased heart rate response to stress. The exaggerated heart rate response observed...

HT2 Receptor Agonist Challenge

M-Chlorophenylpiperazine (mCPP) is an increasingly widely used 5-HT challenge which increases body temperature, stimulates PRL and ACTH cortisol secretion and causes anxiety with GH stimulation occurring after intravenous but not oral administration.61,62 It is non-selective in its binding to 5-HT receptors,63,64 but animal studies suggest that many of its agonist effects are mediated by 5-HT2C receptors.65 mCPP's postsynaptic site of action has been challenged in animals by an in vivo microdialysis finding that it releases 5-HT and that the 5-HT reuptake inhibitor, fluoxetine, blocks this effect and partially attenuates mCPP-mediated PRL release.66 There are however contradictory reports about mCPP's affinity for the human brain 5-HT transporter,64,67 possibly related to different methodologies. In humans, the PRL, cortisol and anxiety responses are antagonized by non-selective 5-HT antagonists68,69 and by ritanserin70 as well as clozapine,71,72 but not by the 5-HT3 antagonist, HCl...

Coping Styles of Differing Personalities

The effects of personality on illness may be mediated by differences in the coping styles adopted by dissimilar personality types. Michael Antoni (1987) found that persons who adopt more passive approaches to distressing events trigger a different set of neurological and endocrine reactions than persons who cope more actively. The helplessness, hyper vigilance, and withdrawal tendencies typical of passive coping are associated with much higher concentrations of cortisol, a stress hormone indicted for its negative effects on immune functioning. It seems that high levels of circulating cortisol sustained over long periods of time kill immune cells and hasten age-related memory loss. Elevated levels of cortisol are frequently found in persons experiencing depression, and chronic depression is associated with higher rates of morbidity and mortality. Thus, passive copers may be conducting chemical warfare against their own bodies.

Hormones Mood and Cognition

Most hormones play a significant role in affect and cognition. An example is cortisol, which is secreted by the adrenal cortex under the influence of the anterior pituitary peptide adrenocorticotropin hormone (ACTH). Cortisol hypersecretion, such as in Cushing's disease, produces psychological changes ranging from hyperphagia, insomnia, and euphoria to anxiety, panic, and mania. On the other hand, a significant number of individuals diagnosed with major depression present signs of adrenal hypertrophy and increased circulating levels of cortisol. The mechanisms hypothesized to mediate increased cortisol levels in clinically depressed patients have implicated increased activity at the level of the hypothalamus, and dysregulation of brain serotonergic and noradrenergic systems. A reduction of circulating cortisol levels, observed in patients with Addison's disease (adrenal atrophy and insufficiency), is itself correlated with irritability, apprehension, mild anxiety, and inability to...

Intergenerational Transmission

In a study of risk factors for the development of PTSD, Yehuda and her colleagues examined the association between cortisol and PTSD in children of holocaust survivors. Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. They concluded that parental PTSD is associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. They suggested that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms (Yehuda et al., 2000).

Further Comment on Risk Factors

Hormones There is a very substantial literature on the relationships between hormone levels and thrombosis. The vast majority of this literature pertains to sex hormones used e.g. for oral contraception or hormone replacement therapy, and this matter was discussed briefly in Chapter 3. However, perturbed thyroid hormone levels also appear to increase the likelihood of DVT (as well as atherosclerosis) the mechanisms remain elusive (Squizzato et al. 2005), but protein C levels may be abnormally low (Nagumo et al. 2007). According to an intriguing recent paper, leptin increases TF production by peripheral monocytes, suggesting a possible reason why obesity is a 'risk factor' for DVT (Napoleone et al. 2007).

Cluster headaches migrainous neuralgia

These are often intense, occur unilaterally around the eye, and are associated with lachrymation, nasal discharge and facial vasodilatation. They are 10 times more common in males than in females, occur particularly between the ages of 40 and 60 years and last for 30-180 min. They are most frequent in spring and autumn when the change in the length of exposure to light is greatest, and are also associated with low plasma peak melatonin and cortisol concentrations.

Evolutionary Considerations

Earlier accounts of allostasis overlooked our evolutionary context. When in our evolutionary past have we had prolonged periods of restfulness (Wingfield and Ramenofsky, 1997 Wingfield and Romero, 2001) We need to take evolution into account as we consider homeostasis, stress, allostasis, and allostatic overload. For example, high levels of corticosterone can favor or support animals in a wide variety of contexts in a number of species, levels of corticosterone or cortisol can be adjusted in the short term by both behavioral and physiological means (Wing-field and Ramenofsky, 1997). In the short term, glucocorticoids are protective and facilitate normal physiological and behavioral adaptation. But in the long run, high levels of corticosterone interfere with a number of regulatory functions (McEwen, 1998a, b, 2000).

Functions of the Glucocorticoids

Effects of treating sodium-depleted dogs with an angiotensin-converting enzyme (ACE) inhibitor for 7 days to block formation of angiotensin II (Ang II) and of infusing exogenous Ang II to restore plasma Ang II levels after ACE inhibition. Note that blocking Ang II formation reduced plasma aldosterone concentration with little effect on cortisol, demonstrating the important role of Ang II in stimulating aldosterone secretion during sodium depletion. (Drawn from data in Hall JE, Guyton AC, Smith MJ Jr, Coleman TG Chronic blockade of angiotensin II formation during sodium deprivation. Am J Physiol 237 F424, 1979.) At least 95 per cent of the glucocorticoid activity of the adrenocortical secretions results from the secretion of cortisol, known also as hydrocortisone. In addition to this, a small but significant amount of glu-cocorticoid activity is provided by corticosterone.

Basis for Sports Nutrition Interest 1 Insulinomimetic Actions

In the experiments showing that vanadium had a beneficial effect on bone, the amounts of vanadium used in supplemented animals and cells were high relative to those that may be needed nutritionally. For example, in the chick and goat deprivation studies, the supplemented controls were fed diets containing 0.5-3.0 mg V kg apparent nutritional deficiency signs required feeding diets containing less than 25 g kg diet.218 The diets used may have been unbalanced in some nutrients.216 Thus, one cannot dismiss the possibility that the high vanadium supplementation was acting pharmacologically to overcome bone changes induced by something other than a simple vanadium deficiency. Such a possibility is supported by the finding that a 0.5-mg V kg diet increased plasma cortisol in guinea pigs, which indicates that vanadium was a stressor, or acting in a non-nutritional manner.219 These guinea pigs also exhibited increased bone calcium and magnesium concentrations. Further study is required to...

Testing for Adrenal Deficiency

Sometimes, deficiency of the adrenal gland can cause an insidious and gradually severe fatigue. There are two tests that can be done to check for this. The simplest test is called a cosyntropin (Cortrosyn) stimulation test. Cosyntropin is a drug that is similar to ACTH (adrenocorticotropic hormone), a hormone made by the pituitary gland to stimulate the adrenal gland, much like TSH stimulates the thyroid gland. To do this test, your physician obtains a blood test for cortisol, then gives you an injection of cosyntropin. Your cortisol level is checked after thirty minutes, and then after another thirty minutes (an hour in total). Normal adrenal glands will be able to produce a cortisol level greater than 20 after the cosyntropin injection. If the cortisol level does not rise sufficiently, then it may be necessary to take cortisol replacement therapy for life. Three different steroid drugs can be used for cortisol replacement therapy, the two best being hydrocortisone and cortisone...

Suprachiasmatic Nucleus

When free-running experiments are extended for a long time, some vegetative functions, such as body temperature, cortisol secretion, and REM sleep, desynchronized from the behavioral functions such as motor activity or food and drink intake, which continue to follow the SCN rhythm. This phenomenon, described as ''internal desynchronization,'' suggested the existence of other different endogenous clocks, and a strong dependence of behavioral input to the SCN rhythm. The existence of these different endogenous pacemakers and this possible hierarchical relationship with the SCN is still debated (37).

Organization of the Cell

The principal fluid medium of the cell is water, which is present in most cells, except for fat cells, in a concentration of 70 to 85 per cent. Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. Chemical reactions take place among the dissolved chemicals or at the surfaces of the suspended particles or membranes.

Increased Uterine Excitability Near Term

Effect of Fetal Hormones on the Uterus. The fetus's pituitary gland secretes increasing quantities of oxytocin, which might play a role in exciting the uterus. Also, the fetus's adrenal glands secrete large quantities of cortisol, another possible uterine stimulant. In addition, the fetal membranes release prostaglandins in high concentration at the time of labor. These, too, can increase the intensity of uterine contractions.

Chemical Structure and Synthesis of Hormones

Steroids secreted by the adrenal cortex (cortisol and aldosterone), the ovaries (estrogen and progesterone), the testes (testosterone), and the placenta (estrogen and progesterone). Cortisol Cholecystokinin (CCK) Leptin hormones (cortisol, androgens, and aldosterone) Promotes development of the female breasts and Peptide

Regulation of Aldosterone Secretion

The regulation of aldosterone secretion by the zona glomerulosa cells is almost entirely independent of the regulation of cortisol and androgens by the zona fas-ciculata and zona reticularis. Figure 77-4 shows the effects on plasma aldosterone concentration caused by blocking the formation of angiotensin II with an angiotensin-converting enzyme inhibitor after several weeks of a low-sodium diet that increases plasma aldosterone concentration several-fold. Note that blocking angiotensin II formation markedly decreases plasma aldosterone concentration without significantly changing cortisol concentration this indicates the important role of angiotensin II in stimulating aldosterone secretion when sodium intake and extracellular fluid volume are reduced.

Regulation of Food Intake and Energy Storage

Hypothalamus Food Intake Regulation

Feedback mechanisms for control of food intake. Stretch receptors in the stomach activate sensory afferent pathways in the vagus nerve and inhibit food intake. Peptide YY (PYY), cholecys-tokinin (CCK), and insulin are gastrointestinal hormones that are released by the ingestion of food and suppress further feeding. Ghrelin is released by the stomach, especially during fasting, and stimulates appetite. Leptin is a hormone produced in increasing amounts by fat cells as they increase in size it inhibits food intake. As discussed later, these neurons appear to be the major targets for the actions of several hormones that regulate appetite, including leptin, insulin, cholecys-tokinin (CCK), and ghrelin. In fact, the neurons of the arcuate nuclei appear to be a site of convergence of many of the nervous and peripheral signals that regulate energy stores. Leptin Cortisol Control of energy balance by two types of neurons of the arcuate nuclei (1) proopiomelanocortin (POMC) neurons that...

Other Antidepressants

Monoamine oxidase inhibitors (MAOIs) increase the PRL response to TRP106 and the cortisol response to 5-HTP107 in depressed patients suggesting they may increase 5-HT1A 5-HT2 receptor function but more specific challenge data are unavailable. Antidepressants which lack both 5-HT and noradrenaline reuptake inhibition such as mianserin and trazodone do not enhance the PRL response to TRP108,109 indicating that this is not a universal property of antidepressant drugs. Nefazodone, related to trazodone and with a similar pharmacology, increases PRL concentrations and temperature when given acutely, an action attributed to its metabolite mCPP.110 Chronic treatment with nefazodone results in decreased responses to acute nefazodone challenge suggesting decreased 5-HT2C receptor sensitivity111 which is similar to the blunted responses to mCPP challenge seen following repeated mCPP administration.112 Lithium has antidepressant properties and has been investigated in a number of studies. PRL...

Coordination of Body Functions by Chemical Messengers

Secondary Endocrine Tissues

Cytokines are peptides secreted by cells into the extracellular fluid and can function as autocrines, paracrines, or endocrine hormones. Examples of cytokines include the interleukins and other lymphokines that are secreted by helper cells and act on other cells of the immune system (see Chapter 34). Cytokine hormones (e.g., leptin) produced by adipocytes are sometimes called adipokines.

Regulation of Energy Release from Triglycerides

Also important are several hormonal changes that take place to promote rapid fatty acid mobilization from adipose tissue. Among the most important of these is a marked decrease in pancreatic secretion of insulin caused by the absence of carbohydrates. This not only reduces the rate of glucose utilization by the tissues but also decreases fat storage, which further shifts the equilibrium in favor of fat metabolism in place of carbohydrates. Probably the most dramatic increase that occurs in fat utilization is that observed during heavy exercise. This results almost entirely from release of epinephrine and norepinephrine by the adrenal medullae during exercise, as a result of sympathetic stimulation. These two hormones directly activate hormone-sensitive triglyceride lipase, which is present in abundance in the fat cells, and this causes rapid breakdown of triglycerides and mobilization of fatty acids. Sometimes the free fatty acid concentration in the blood of an exercising person...

Synthesis and Secretion of Adrenocortical Hormones

Synthesis Cortical Hormones

The zona fasciculata, the middle and widest layer, constitutes about 75 per cent of the adrenal cortex and secretes the glucocorticoids cortisol and Aldosterone and cortisol secretion are regulated by independent mechanisms. Factors such as angiotensin II that specifically increase the output of aldosterone and cause hypertrophy of the zona glomerulosa have no effect on the other two zones. Similarly, factors such as ACTH that increase secretion of cortisol and adrenal androgens and cause hypertrophy of the zona fasciculata and zona reticularis have little or no effect on the zona glomerulosa. Once the cholesterol enters the cell, it is delivered to the mitochondria, where it is cleaved by the enzyme cholesterol desmolase to form pregnenolone this is the rate-limiting step in the eventual formation of adrenal steroids (Figure 77-2). In all three zones of the adrenal cortex, this initial step in steroid synthesis is stimulated by the different factors that control secretion of the...

Consequences of Sleep Deprivation

With the exception of thyroid hormones, appreciable hormonal alterations have not been observed after total SD, including catecholamine, cortisol, or sex hormone levels (85). With partial SD, impaired glucose tolerance, elevated evening cortisol levels, and thyroid function abnormalities have been reported (79). Sleep loss can alter the pattern of secretion of hormones under circadian influence. For example, selective deprivation of SWS can diminish the secretion of growth hormone (86).

Primary Essential Hypertension

Sympathetic nerve activity, especially in the kidneys, is increased in overweight patients. The causes of increased sympathetic activity in obesity are not fully understood, but recent studies suggest that hormones, such as leptin, released from fat cells may directly stimulate multiple regions of the hypothalamus, which, in turn, have an excitatory influence on the vasomotor centers of the brain medulla.

Effect Of Spirulina On Fatty Liver

Fatty liver is a common cause of chronic liver disease and refers to accumulation of excess fat in the liver. It is diagnosed that if fat exceeds 5 of the total weight of normal liver or when more than 30 of the hepatocytes in a liver lobule have lipid deposits, most of the fat that accumulates in the liver is triacylglycerols and fatty acids other forms of fat, such as cholesterol, cholesterol ester, and phospholipids, are also present. Fatty liver is often associated with alcoholic liver disease, hyperinsu-linemia, and insulin-resistance. Accordingly, it is most often observed in alcoholics, obese persons, and diabetic patients. It is also frequently caused by drugs,83 viral hepatitis,84 chemical intoxication,85 pregnancy,86 intestinal bypass surgery,87 and malnutrition.88 Histological findings reveal that fat deposits in the liver may vary in size and distribution. Hepatocytes may contain large fat droplets with an anomalously displaced nucleus (macrovesicular type) or multiple...

Biological Clocks And Seasonal Behavior

The human rhythms are represented mainly by circa-dian and circannual rhythms, characterized, respectively, by a period of 21 to 27 hours and a longer period of more than 27 hours, such as a month or season. The human cir-cadian system is composed of at least two oscillators, which are self-sustained and coupled to each other. One of these oscillators is strong and controls body temperature, REM-sleep propensity, and cortisol secretion the other is weak and controls the sleep-wake cycle and sleep related neuroendocrine activity. These oscillator systems may be affected by many factors such as organic diseases, drugs, and environmental factors, which may lead to psychological disorders.

Normal and Pathological Facilitation of Parturition by a Feedforward Endocrine Mechanism

Let me begin with a question Why the study of preterm delivery of babies in a book on allostatic regulation There are several reasons. First, placental CRH is elevated during adverse events in pregnancy. It may be a predictor of preterm labor when there are conditions of adversity (see, e.g., Wolfe et al., 1988 Goland et al., 1993 Wadhwa et al., 2001). Second, a positive feedback loop underlies parturition, providing an allostatic mechanism namely, cortisol increases CRH gene expression in the placenta under normal conditions. And third, this feedback loop may be exaggerated during adverse conditions (allostatic overload ). In the case of adverse events in pregnancy such as infections, metabolic stress, and social stress, CRH may be overexpressed in the placenta. Similarly, in the case of fear and anxiety, CRH may be altered in the brain (Gold et al., 1984 Nemeroff et al., 1984 Nemeroff, 1992) or with a sense of potential harm (Kalin et al.,

Premenstrual Dysphoric Disorder and 5HT

Neuroendocrine challenge provides another method for probing the integrity of the serotonergic system in PMDD women. Administration of tryptophan to women with PMDD produced a blunted growth hormone and cortisol response compared to the response found in control women. These differences were detected during both phases of the menstrual cycle,39 suggesting that trait differences exist between PMDD patients and controls. When the prolactin response to tryptophan administration was evaluated, blunting occurred only during the premenstrual phase in this same group of symptomatic women. The more selective 5-HT1A partial agonist, buspirone, also led to a blunted prolactin response in PMDD patients compared to controls.40 However, women were tested only during the follicular phase, which is when the difference was detected. It is not known whether this partial agonist would have caused blunting in the luteal phase also. Two groups have investigated the prolactin response using a different...

General Adaptation Syndrome

The General Adaptation Syndrome (GAS) is a cluster of bodily responses to severe, prolonged stressors that was described by Hans Selye. Selye observed that rats exposed to a wide variety of noxious agents exhibited a nonspecific syndrome consisting of enlargement of the adrenal cortex shrinkage of the thymus, spleen, and lymph glands and the appearance of ulcers in the stomach and small intestine. This response was seen in animals exposed to extreme cold and heat, intense sound or light, forced exercise, injections of various organ extracts or formalin, or a variety of other intense biological challenges to normal homeostatic function. Selye suggested that the GAS consisted of three phases of response to a stressor. The initial stage consisted of an alarm reaction during which the adrenal cortex enlarged and released large amounts of the adrenoglucocorticoid hormone cortisol into the bloodstream, the lymphatic tissues shrunk, the number of white blood cells declined, the...

Physiological Transport Mechanisms for Peptides and Proteins at the Blood Brain Barrier

The concept of saturable, receptor-mediated uptake systems for peptides and proteins at the blood-brain barrier has evolved over the last two decades. There is now combined evidence from in vitro and in vivo studies, at the biochemical and pharmacokinetic levels as well as at the morphological level, that peptides are transported across the endothelial cells. This includes transport of compounds as structurally diverse as insulin and insulin-like growth factors (IGF-I and II) (56), transferrin (57), low density lipoprotein (LDL) (58), and leptin (59). The overall process of transendothelial passage is designated as transcytosis and is composed of binding to a luminal plasma membrane receptor, endocytosis, transfer through the endothelial cytoplasm to the abluminal side, and abluminal exocytosis into brain interstitial space (60). Recently, substantial evidence has been accumulated to support the presence at the BBB of a transport system that is involved in the transcytosis of leptin....

Conclusion Adaptation Allostasis and Anticipation

Allostasis and Cortisol The Hormone of Energy Metabolism Cortisol, as I have indicated, has permissive, stimulatory, sup-pressive, and preparative functions in orchestrating bodily viability to acute challenges (Ingle, 1952 Munck et al., 1984 McEwen, 1998a, b Sapolsky et al., 2001). Glucocorticoids regulate cardiovascular, metabolic, and neural adaptive functions in the short-term context in a wide variety of ways (Sapolsky et al., 2000). Social rank is one instance in which cortisol is clearly linked to behavioral expression. Social ranking and attachment have profound effects on internal physiology (Herbert, 1993 Gunnar, 1998 Sapolsky, 2000). In addition, cognitive factors, such as determining what is a real threat from what might not be, can determine cortisol levels baboons who were less able to determine the real from the not real had higher levels of cortisol and perhaps chronic arousal (figure C.1 Sapolsky, 2000). But more generally, baboons with elevated levels of cortisol...

Pathophysiology of DHEA deficiency

Mary adrenal insufficiency manifest signs and symptoms associated with a deficiency or absence of all adrenal cortical hormones including cortisol, DHEA, and aldosterone 283,284 . Women with panhypopituitarism have severe androgen deficiency due to a lack of both ovarian and adrenal androgen production 248 . Pituitary insufficiency can lead to a deficit of DHEA as the zona reticularis of the adrenal gland produces DHEA in response to stimulation by pituitary ACTH, similar to the stimulation of DHEA in the Leydig cell by LH 286 . Various drugs can contribute to decreased circulating levels of DHEA. Exogenous corticosteroids can decrease adrenal DHEA synthesis via negative feedback to the hypothalamus and pituitary gland, decreasing corticotropin-releasing hormone (CRH) and ACTH secretion, respectively. Both adrenolytic drugs, such as mitotane, and inhibitors of corticos-teroid synthesis, such as ketoconazole, can reduce adrenal production of DHEA along with cortisol 295,296 .

Job Stress and Strain and Blood Pressure

In a comprehensive study addressing the relation between job strain, as assessed using the Karasek model, on nurses, Fox, Dwyer, and Ganster (1993) obtained measures of both subjective job strain (from nurse self-reports) and objective job demands (from ratings of patient load, number of deaths witnessed, and percentage of patient contact as determined by nursing supervisor ratings). Although subjective measures of job strain were related to SBP and cortisol measured at work and both SBP and DBP at home, the univariate correlations between measures of job stress and blood pressure were higher for objective

Release of Energy from Glucose by the Pentose Phosphate Pathway

In almost all the body's muscles, essentially all the carbohydrates utilized for energy are degraded to pyruvic acid by glycolysis and then oxidized. However, this gly-colytic scheme is not the only means by which glucose can be degraded and used to provide energy. A second important mechanism for the breakdown and oxidation of glucose is called the pentose phosphate pathway (or phosphogluconate pathway), which is responsible for as much as 30 per cent of the glucose breakdown in the liver and even more than this in fat cells.

Biosynthesis of adrenal androgens

Surge at the time of adrenarche (between the sixth and tenth years of life), maximum levels during the third decade of life, and a gradual decline to about 10-20 of maximum values by the seventh or eighth decade of life 268,269 . While serum DHEA-S concentration does not vary throughout the day, DHEA secretion follows a diurnal pattern similar to that of cortisol 270,271 . Figure 18.6 depicts the synthesis and metabolism of DHEA. DHEA itself is synthesized from 17-OH pregnenolone via conversion by the 17-20 lyase portion of the enzyme P450c17. Subsequently, DHEA is converted to androstenedione by the enzyme 3P-hydroxysteroid dehydrogenase (3P-HSD). Finally, androstenedione is converted to T by the enzyme 17P-OH hydroxysteroid dehydrogenase (17P-HSD), and subsequently to estrogen by the enzyme aro-matase 233-235,270-272 . An important requirement for DHEA action is the ability of DHEA and DHEA-S to continuously interconvert, via the enzyme sulfotransferase, as only unsulfated DHEA can...

Hormonal Response in Posttraumatic Stress Disorder

In a well-functioning person, stress produces rapid and pronounced hormonal responses. However, chronic and persistent stress inhibits the effectiveness of the stress response and induces desensitization. PTSD develops following exposure to events that overwhelm the individual's capacity to reestablish homeostasis. Instead of returning to baseline, there is a progressive kindling of the individual's stress response. Initially only intense stress is accompanied by the release of endogenous, stress-responsive neurohormones, such as cortisol, epinephrine, norepinephrine (NE), vasopressin, oxytocin, and endogenous opioids. In PTSD even minor reminders of the trauma may precipitate a full-blown neuroendocrine stress reaction It permanently alters how an organism deals with its environment on a day-to-day basis, and it interferes with how it copes with subsequent acute stress. A review of the neuroendocrine findings in PTSD to date shows very specific abnormalities in this disorder,...

Normal Hypothalamic Pituitary Axis

Diagrammatic Representation Pituitary

Growth hormone (GH) is a 191-amino acid polypeptide synthesized and secreted by the somatotrophs in the anterior pituitary gland in response to the hypothalamus releasing hormones, primarily GH-releasing hormone (GHRH) and somatostatin. GHRH secretion is usually steady, whereas somatostatin secretion is interrupted intermittently. Somatostatin contributes to the synthesis of GH in the pituitary but, paradoxically, inhibits GH release 45 . When somatostatin concentrations decrease, the tonic concentration of GHRH causes the release of GH into the systemic circulation. Factors such as neuropeptide Y, leptin, galanin, and ghrelin may also regulate GH secretion. In healthy children and adults, GH secretion is pulsatile, particularly during sleep,with two to six pulses per night 50 . In adolescents, additional pulses occur during the day, and the pulses have higher peaks than those seen in children and adults (Fig. 5.2 a). a Changes with pubertal status in the normal daily pattern of...

Valve Pathology The Formation of Nascent Thrombi within VVP

Muscle contents of the valve sinus decrease and fat deposits increase. We may speculate about the significance of these findings for the increased incidence of DVT in older people the cusp becomes less flexible, impairing the efficiency of valve function. In addition, perhaps the lower resting venous tone in older patients decreases local blood velocity, exacerbating underperfusion by attenuating the intravascular pressure changes during pulsatile flow (see below).

Chronic Angst Allostasis and Pathology

Provide physiological and behavioral resources that help maintain equilibrium. Unfortunately, these resources are finite. Chronic signals from physiological mediators (cytokines, cortisol, catecholamines, etc.) take their toll on bodily function, resulting in vulnerability to a variety of diseases such as those that concerned Sterling and Eyer (1988) and later McEwen and Seeman (1999 including hypertension, diabetes, atherosclerosis, bone loss, sleep disruption, disruption of immune and reproductive functions, inhibition of neurogenesis, aging process Seeman et al., 2001). Vulnerability to these events can occur from prenatal events (Barker, 1997 Welberg and Seckl, 2001).

Precocious Development

Recent studies have suggested that nutrition and body composition may influence the development of reproductive competence in mammals. Witchel, Arslanian, & Lee (1999) reported no significant relationships between circulating gonadotropin and leptin concentrations. This is important as prior assumptions held that leptin concentrations communicated nutritional status to the neuroendrocrine reproductive axis (Heger, Partsch, Peter, Blum, Kiess, & Sippell, 1999). Gonadotropin-releasing hormone (GnRH) is linked to precocious anatomical development in males and females. GnRH agonist treatment remains controversial, although there is some attempt to standardize treatment protocols (Partsch & Sippell, 2002). Cherniske, E. M., Sadler, L. S., Schwartz, D., Carpenter, T. O., & Pober, B. R. (1999). Early puberty in Williams syndrome. Clinical Dysmorphia, 8(2), 117-121. Della Manna, T., Setian, N., Damiani, D., Kuperman, H., & Dicht-chekenian, V. (2002). Premature thelarche...

Not broken but not working properly

If this were the case, it would be difficult to understand why antidepressant drugs that raise monoamine levels quickly take several weeks to have a significant effect on depressive symptoms. This delay suggests that antidepressants work indirectly and that depression is caused by biochemical dysfunction that is only distantly linked to monoamine function. Indeed, in their search for new targets for antidepressant drugs, pharmaceutical companies are now exploring alternative biochemical pathways, such as those associated with the regulation of the brain's stress hormone cortisol. Growing concerns about the safety and side effects of the monoamine uptake inhibitors are a driving force behind the search for more effective new treatments for this baffling illness of the brain.

Physiological Basis of Sleep and Wakefulness

Several anabolic hormones, such as growth hormone, are secreted primarily during sleep, whereas catabolic hormones, such as cortisol, are produced mainly during wakefulness. The metabolic rate slows during NREM sleep, in which energy is conserved, the body temperature falls, and protein synthesis and other anabolic processes are accentuated.

Formation of Carbohydrates from Proteins and Fats Gluconeogenesis

Diminished carbohydrates in the cells and decreased blood sugar are the basic stimuli that increase the rate of gluconeogenesis. Diminished carbohydrates can directly reverse many of the glycolytic and phosphogluconate reactions, thus allowing the conversion of deaminated amino acids and glycerol into carbohydrates. In addition, the hormone cortisol is especially important in this regulation, as follows. When the glycogen-storing cells (primarily liver and muscle cells) approach saturation with glycogen, the additional glucose is converted into fat in liver and fat cells and is stored as fat in the fat cells. Other steps in the chemistry of this conversion are discussed in Chapter 68. Effect of Corticotropin and Glucocorticoids on Gluconeogenesis. When normal quantities of carbohydrates are not available to the cells, the adenohypophysis, for reasons not completely understood, begins to secrete increased quantities of the hormone corti-cotropin. This...

Neuroscience Perspectives

Many studies of the anxiety and stress response have implicated key hormones and neurotransmitters. Prominent among these are corticotropin-releasing hormone (CRH), which modulates adrenal cortisol response norepinephrine, which controls the ratio of signal to noise, thereby alerting the organism to the relevance of certain stimuli and serotonin, which plays a key braking role in controlling sensory input to the amygdala as well as modulating anxiety responsivity. Brain norepinephrine synergizes with CRH in activating arousal of the peripheral sympathetic nervous system and central nervous system, the amygdala plays a key role in orchestrating this response, and these hormones may provide feedback to the amygdala that potentiates the anxiety response. There are significant genetic contributions to anxiety (Plomin, DeFries, McClearn, & Rutter, 1997). Twin studies have shown heritability in children for a dimension of fear-fulness called behavioral inhibition, as well as shyness, and...

Possible Mechanisms for Blunted GH Secretion to GH Secretagogues in Anxiety and Mood Disorders

Clonidine, varies inversely with the degree of HPA axis activation. More recent work with nonhuman primates has provided even stronger evidence of a negative correlation between CRF and GH secretion (Coplan et al., 2000a). Examining juvenile neurochemical levels of CSF, CRF, 5 hydroxy-indole-acetic acid (serotonon metabolite) (5-HIAA), HVA, SOM, 3-methoxy-4-hydroxy phenylglycol (noradrenaline metabolite) (MHPG), and CSF cortisol revealed that only levels of CSF and CRF were significantly correlated with GH response to clonidine. An inverse relationship involving the CRF and HPA axis and GH may be an enduring, trait-like feature observed in association with both stressful early rearing and Mood and Anxiety Disorders.

Gestational Thyroid Disease Thyroid Disease During Pregnancy

Just as in the general population, pregnant women can develop hypothyroidism or thyrotoxicosis for other reasons, discussed in Chapters 3 and 4. But what does seem clear (at least to thyroid researchers) is that pregnancy increases your body's thyroid hormone requirements. Pregnancy may lead to relative iodine deficiency, which can increase the severity of preexisting hypothyroidism, and worsen preexisting Hashimoto's or Graves' disease. Finally, it can unveil overt hypothyroidism in women who had subclinical hypothyroidism prior to pregnancy. In some rare cases, if there is a great deal of bleeding during delivery, the pituitary may be damaged (Sheehan's syndrome) and result in hypothyroidism, loss of cortisol from the adrenal gland, and infertility.

Evaluation Guidelines Table82

When visual loss due to a sellar process is suspected, pituitary and hypothalamic function should be evaluated. The basic outpatient endocrinological panel should include serum prolactin, growth hormone (GH) (after a 75-g oral glucose load), insulin-like growth factor-I, adrenocorticotropic hormone (ACTH), cortisol (serum morning sample or 24-hour urine free cortisol), thyroid-stimulating hormone (TSH), T3, T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone level. Low values, and even normal ones in some instances, are consistent with hypopituitarism. High values imply pituitary hypersecretion by a pituitary adenoma.

Endogenous Substances Single Protein Analysis 9411 Hormones and Growth Factors

Leptin is a hormone that plays a central role in food intake and energy expenditure (Macajova et al., 2004). Systemic levels of leptin are increased in obese individuals, and have been found to stimulate the growth of breast cancer cells in vitro. Leptin levels in NAF were more readily measured in post- than in premeno-pausal women and were significantly higher in postmenopausal women with a body mass index (BMI) < 25 (Sauter et al., 2004a). While NAF leptin levels were not associated with pre- or postmenopausal breast cancer, they were associated with premenopausal BMI.

Physiological effects

The serum level of noradrenaline is raised throughout the night in those with insomnia, particularly when their sleep efficiency is low, and it is likely that sympathetic activity is increased throughout the day as well. The ACTH level is raised throughout the day and night and there is a significant increase in plasma cortisol IL-6, and TNF alpha levels are increased, particularly in the daytime, but also during sleep.

Hormonal Responses to Emotional Stress

The adrenal cortex also is involved in response to either acute (fear) or chronic (anxiety) stress. However, the adrenal cortex is not directly activated by the sympathetic nervous system. As noted earlier, the adrenal cortex is activated by adrenocorticotropic hormone (ACTH). ACTH is released from the adenohypophysis (anterior pituitary) and stimulates the adrenal cortex to release glucocorticoids (cortisol, cortisone, and corticosterone). The glucocorticoids increase cardiac and vascular muscle tone, enhance the release of nutrients into the blood, decrease inflammation, and inhibit protein synthesis. The release of ACTH by the anterior pituitary is controlled by the hypothalamic hormone, corticotropin-releasing factor (CRF). CRF is manufactured by neurons in the paraventricular nucleus of the hypothalamus and is transported down the axons of these neurons and released into the portal circulation of the ade-nohypophysis where it stimulates release of ACTH. The paraventricular...

Seasonal affective disorder SAD

Raised blood level in the mornings despite normal nocturnal secretion. The total sleep time increases, which is unlike other forms of depression, and the duration of both NREM and REM sleep increases, including stages 3 and 4 NREM sleep. The rhythm of cortisol secretion is phase delayed.

Deleterious Cardiovascular Effects of Alcohol

An ethanol intake of as little as 30-40 g day (approximately two to four beers) can have a pressor effect. The effect abates within several days of achieving abstinence. The manner in which this effect is mediated remains obscure. Acute ingestion does not alter plasma concentrations of renin, adrenaline, noradrenalin, aldosterone, or cortisol, and there is no evidence of activation of the sympathetic nervous system (36). It is possible that in some heavy drinkers who are chronically hypertensive, the hypertrophic, less compliant left ventricle could evidence diastolic dysfunction, indirectly leading to yet another type of heart failure.

Summary And Recommendations

Numerous studies have investigated both the effects that exercise has on vitamin C needs and the effect that supplemental vitamin C has on subsequent athletic performance. Several animal and human studies do seem to indicate that strenuous or prolonged exercise or physical training, in all likelihood, increases the need for vitamin C. It is less likely that light or moderate levels of activity and training increase vitamin C requirements. Animal studies consistently show reduced tissue levels of ascorbic acid with exercise. Several human studies have shown reduced plasma and leukocyte concentrations and reduced urinary excretion of the vitamin with exercise. In addition, supplemental dietary vitamin C has been shown to increase adaptation to exercise in the heat and reduce upper respiratory tract infections in individuals undergoing strenuous exercise. Supplemental vitamin C also has been shown, in some studies, to reduce plasma cortisol concentrations and muscle soreness markers...

Tricyclic Antidepressants TCAs

Lesch et al90 report no alteration in the ACTH cortisol response to ipsapirone in depressed patients treated with amitriptyline. With regard to the effect of TCAs on putative 5-HT2-mediated responses to presynaptic pharmacological challenge, Meltzer97 reports that three to six weeks treatment of 14 patients with depressive illness or OCD with a mixed group of TCAs (including 1 patient on maprotiline) has no effect on the cortisol response to 5-HTP. Studies using fenfluramine challenge give inconsistent findings in depressed patients with enhanced PRL responses following treatment with clomipramine, imipramine and amitriptyline29-31 but non-significantly lower responses to a mixed group of antidepressants (mostly TCAs) in another a study.98 In studies using the more noradrenaline-specific reuptake inhibitors, nortriptyline and maprotiline, decreased PRL responses are reported98,99 although only the study with nortriptyline reached statistical significance, and then at five, but not...

The Suprachiasmatic Nucleus

In addition to controlling the circadian variability of the sleep-wake cycle, the SCN creates variability in locomotor activity, food intake, water intake, sexual behavior, core body temperature, and hormonal levels. Thus, cortisol is highest in the early morning hours between 4 00 to 8 00 am, and thyroid-stimulating hormone increases just before sleep. Hormones both influence and are influenced by the circadian clock.

Nocturnal Growth Hormone Secretion

Sleep onset represents a highly evolved, dynamic biological process, involving the reduction and ultimate cessation of noradrenergic and serotonergic neuronal activity, the onset of cholinergic bursts of firing from pontine nuclei and the increased secretion of GH primarily through muscarinic inhibition of SOM, the GH secretagogue suppressant. During the early phases of sleep, increases of spontaneous GH secretion have been associated with slow wave (delta) sleep, the former subsiding several hours following sleep onset. The elevations of CRF and cortisol increases that are frequently evident in Mood Disorders are inhibitory towards GH secretion and imply a ratio increase of CRF to GRF in adult depression (Holsboer, 1994).

HT1 Receptor Agonist Challenge

The azapirones (buspirone, ipsapirone, gepirone) are partial 5-HT1A receptor agonists that stimulate PRL, GH and cortisol secretion and lower body temperature.40 5-HT1A receptors are sited both presynaptically (cell body autoreceptors) and postsynaptically41-44 so that responses to challenge by these compounds could reflect pre- and or postsynaptic receptor stimulation. Pindolol has been shown to antagonize the GH response to buspirone, the cortisol response to ipsapirone and the hypothermic responses to buspirone and ipsapirone45-47 suggesting that these are mediated by 5-HT1A receptors. The PRL response to buspirone is particularly robust but the weight of evidence suggests that this is mediated by blockade of dopaminergic (D2) receptors,48 in particular the failure of pindol to antagonize the response in the same study where GH and hypothermic responses were blocked.45 The GH and cortisol responses are likely to reflect postsynaptic activation but there is controversy as to whether...

Programming Of The Hypothalamopituitaryadrenal Axis

McCance and Widdowson had suggested that the critical influence exerted by nutrition during fetal life would be upon hypothalamic function30. Edwards and colleagues have suggested that blood pressure might be critically determined through the maternal glucocorticoid axis45. In dams given low protein diets, the activity of placental 11 POH-steroid dehydrogenase was reduced by about one third, which would increase the likelihood of fetal over-exposure to maternal glucocorticoids46. The extent to which maternal glucocorticoids might directly contribute to programming fetal metabolism has been explored47. Maternal administration of metyrapone or matemal adrenalectomy during early pregnancy abolishes the effect ofmaternal low protein diets upon the blood pressure of offspring47-48. This provides direct evidence that part of the effect might be attributed to changes in the hypothalamo-pituitary-adrenal axis in the mother and or the fetus. Further support comes from the observations that...

Anterior Lobe or Adenohypophysis

Adrenocorticotropin (ACTH or adrenocorticotropic hormone) stimulates the production and release of hormones by the adrenal cortex (the adrenal glands are above the kidneys). ACTH triggers the release of glucocorticoids (e.g., cortisol), which are important in carbohydrate metabolism and in the body's resistance to stress. ACTH itself is released in response to physical or emotional stress.

Selective Serotonin Reuptake Inhibitors SSRIs

Consistent with the findings described above with TCAs, treatment of depressed patients with the SSRI, fluvoxamine, results in increased PRL responses to TRP present at one week and to an even greater extent at four weeks.86 Probing of 5-HT1A receptor function using ipsapirone, buspirone and gepirone following chronic SSRI treatment gives a consistent picture of blunted cortisol, GH, psychological and hypothermic responses in healthy volunteers and patients with OCD14,101,102 suggesting both pre- and postsynaptic 5-HT1A receptors are desensitized. The blunted GH and psychological responses to buspirone are seen in spite of a three-fold increase in plasma buspirone concentrations.102 These findings are not easily reconciled, but one interpretation is that the balance of effects is enhancement of net 5-HT1A neurotransmission in spite of postsynaptic receptor desensitization. Studies using presynaptic 5-HT2 receptor probes to investigate the effects of SSRIs have not produced entirely...

Adrenal Cortex

The glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and are involved in a myriad of functional responses in the organism. These hormones serve as major regulators of carbohydrate and lipid metabolism, in adaptation to stress in linking sleep and waking states in food-seeking and cognitive behaviors in controlling emotional states in mediating anaphylactic and immune responses in modulating the responses to neurochemicals, hormones, and growth factors and in the differentiation and development of cells (Munck, Guyre, & Holbrook, 1984 Tsigos and Chrousos, 1994). Cortisol is the principal natural glucocorticoid in humans, whereas in many animals corticosterone is the primary glucocorticoid.

Introduction

The relationship between ascorbic acid and exercise has been studied for a number of years, with several review articles having been written covering this topic.1-5 This chapter will further address the knowledge base concerning vitamin C and exercise. Such topics as the basic functions and deficiency symptoms of ascorbic acid as related to exercise will be covered. In addition, articles related to exercise and vitamin C requirements immune function cortisol secretion and stress muscle soreness supplementation and sports performance and intakes needs of physically active persons for the vitamin will be reviewed. Ascorbic acid has several important functions as related to physical activity. The vitamin has long been known to be necessary for normal collagen synthesis. Collagen, one of the most abundant proteins in the body, is a vital component of cartilage, ligaments, tendons and other connective tissue. Vitamin C is needed for the formation of the vitamin-like compound carnitine,...

Photodegradation

In addition, the following photoinduced degradation reactions have been reported hydrolysis of mefloquine,223 furosemide,224 and LY277359 (a derivative of benzofuran carboxamide)225 (Scheme 59) elimination of hydrogen halide from meclofenamic acid226 (Scheme 60) oxidation of a hydroxyl group of 2 l-cortisol tert-butylacetate227 and methanol228 (Scheme 61) and rearrangement of benzydamine229 (Scheme 62). Oxidation of menadione is enhanced by light (Scheme 63).230

Bloodbrain Barrier

The paracellular and transcellular pathways for free solute exchange across the capillary wall that are present in the microcirculation of peripheral organs are absent in the capillaries perfusing the brain and spinal cord. Therefore, circulating molecules gain access to brain or spinal cord by only one of two processes (1) free diffusion based on the lipid solubility and molecular weight of the molecule, and (2) catalyzed transport (Oldendorf, 1974). The latter involves either carrier-mediated transport (CMT) for small molecular weight nutrients such as glucose or amino acids, or receptor-mediated transcytosis (RMT) for certain circulating peptides such as insulin, leptin, or transferrin (Pardridge, 2001). The CMT and RMT systems are individual proteins expressed by specific genes within the capillary endothelium. The CMT and RMT systems mediate the transport of nutrients or some endogenous peptides across both the luminal plasma membrane of the capillary endothelium, at the blood...

Hypothalamic Obesity

Hypothalamic damage from a tumor or cancer treatment can also result in hypothalamic obesity - unrelenting weight gain that does not respond to caloric restriction or exercise - attributable to ventromedial hypothalamus damage and abnormality in leptin, ghrelin and insulin feedback 27 . In rodents, hypo-thalamic obesity can be suppressed by pancreatic vagotomy to prevent insulin hypersecretion. Recent studies in patients with cranial insult confirmed insulin hypersecretion as one of the major mechanisms for the development of hypothalamic obesity 28 . In a study of 148 survivors of childhood brain tumors, the risk factors for hypothalamic obesity included

Hypothyroidism

The standard treatment for TSH deficiency or primary hypothyroidism is levothyroxine replacement therapy (Fig. 5.1 2 d). Thyroid hormone replacement can precipitate clinical decompensation in patients with unrecognized adrenal insufficiency, because levothyroxine treatment may improve the metabolic clearance of cortisol. Thus, it is necessary to evaluate patients for adrenal insufficiency and, if this condition is present, treat it with hydrocortisone before initiating thyroid hormone therapy. In patients who also have ACTH deficiency, we usually initiate cortisol replacement three days before beginning thyroid hormone therapy.

Other conditions

An increase in weight and appetite is an early and often the initial symptom of narcolepsy, particularly in children. It is associated with a reduction in hypocretin production which stimulates appetite, and a reduction in leptin which is an appetite suppressant. Initially there is an increase in appetite, particularly for carbohydrates, but later in the natural history food intake appears to be reduced, although some subjects retain a craving for carbohydrate food during the night. The fall in serum leptin is probably due to a reduction in sympathetic activity and there is also a loss of the nocturnal increase in leptin. In general, carbohydrates appear to have a tendency to promote sleep in narcolepsy.

Glands And Behavior

The remaining endocrine glands are the pancreas, thyroid, and parathyroid. The endocrine pancreas secretes insulin necessary for glucose and fats to enter cells so that the cells can use them for energy or, in the case of fat cells, store them. The thyroid gland secretes thyroxin, which regulates metabolic rate and protein synthesis by cells throughout the body. The parathyroid secretes a hormone involved in the regulation of calcium concentration in blood. This gland has little direct influence on behavior.

Meal Size

Other feedbacks unrelated to the ongoing meal also control meal size. Most interesting are two hormones whose average blood levels are correlated with body fat content, insulin and leptin. The control of meal size and food intake by body fat can be dramatic or weak, depending, for example, on genetic variation, on the availability, palatabil-ity, variety, and energy density of food, and, probably, on conditioning.

Hirsutism

Androgen excess and drug-induced hirsutism must be ruled out. Tests for dehydroepiandrosterone sulfate, testosterone, follicle-stimulating hormone luteinizing hormone ratio, and prolactin help rule out endocrinologic causes. Androstenedione, cortisol, sex hormone-binding proteins, and 17-hydroxyprogesterone levels may also be obtained, depending on clinical suspicion.

Steroidogenic Cells

Another endocrine gland susceptible to destruction by autoimmunity, infection, and bleeding is the adrenal gland. Because oral replacement of cortisol does not accurately reproduce the pattern of cortisol secretion by the native adrenal gland, the generation of adrenal cells from stem cells would be of therapeutic benefit.

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