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...

Trouble Spot Nutrition Overview

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Cortisol and Growth Hormone

Growth hormone (GH) and Cortisol are thought to become important glucose-raising hormones only after hypoglycaemia has been prolonged for more than one hour. However, defects in Cortisol and GH release can cause profound and prolonged hypoglycaemia because of a reduction in hepatic glucose production and, to a lesser extent, by exaggeration of insulin-stimulated glucose uptake by muscle. Abnormalities in growth hormone and cortisol secretion in response to hypoglycaemia are characteristic of long-standing type 1 diabetes, affecting up to a quarter of patients who have had diabetes for more than ten years. In rare cases, coexistent endocrine failure such as Addison's disease or hypopituitarism also predisposes patients to severe hypoglycaemia. Pituitary failure, although uncommonly associated with type 1 diabetes, occasionally develops in young women as a consequence of ante-partum pituitary infarction. As an intact hypothalamic-pituitary-adrenal axis is important for adequate...

Obesity Cortisol Metabolism

Cortisol is subjected to metabolic transformations in the periphery, which are of importance for the impact of cortisol on peripheral target tissues. This area is reviewed in the chapter by Walker and Seckl (Chapter 18), where detailed references can be found, and is only discussed here in relation to the central perturbations of HPA axis activity, reviewed in the preceding section. There are two main systems regulating cortisol metabolism. One is the 5a reductases which transfer cortisol to tetrahydrocortisone, which is an essentially inactive metabolite excreted in the urine. The other system is the 11 -hydroxysteroid dehyd- rogenases (HSD), which consist of the HSD1, converting cortisone to Cortisol, and the HSD2, converting Cortisol to cortisone. In humans cortisone is a much less powerful glucocorticoid than cortisol. There is evidence for an increased activity in obesity of 5a-reductase and HSD2, which inactivates cortisol. This would be expected to result in less active...

Cortisol Signals Stress Including Low Blood Glucose

A variety of stressors (anxiety, fear, pain, hemorrhage, infections, low blood glucose, starvation) stimulate release of the corticosteroid hormone cortisol from the adrenal cortex. Cortisol acts on muscle, liver, and adipose tissue to supply the organism with fuel to withstand the stress. Cortisol is a relatively slow-acting hormone that alters metabolism by changing the kinds and amounts of certain enzymes synthesized in its target cell, rather than by regulating the activity of existing enzyme molecules. In adipose tissue, cortisol leads to an increase in the release of fatty acids from stored TAGs. The fatty acids are exported to serve as fuel for other tissues, and the glycerol is used for gluconeogenesis in the liver. Cortisol stimulates the breakdown of muscle proteins and the export of amino acids to the liver, where they serve as precursors for gluconeogenesis. In the liver, cortisol promotes gluconeogenesis by stimulating synthesis of the key enzyme PEP carboxykinase (see...

The Leptin System May Have Evolved to Regulate the Starvation Response

Although much of the initial interest in leptin resulted from its possible role in preventing obesity, the leptin system probably evolved to adjust an animal's activity and metabolism during periods of fasting and starvation, not to restrict weight. The reduction in leptin level triggered by nutritional deficiency reverses the thermo-genic processes illustrated in Figure 23-32, allowing fuel conservation. Leptin activates AMP-dependent protein kinase (AMPK), which regulates many aspects of fuel metabolism. Leptin also triggers decreased production of thyroid hormone (slowing basal metabolism), decreased production of sex hormones (preventing reproduction), and increased production of glucocorti-coids (mobilizing the body's fuel-generating resources). By minimizing energy expenditures and maximizing the use of endogenous reserves of energy, these leptin-mediated responses may allow an animal to survive periods of severe nutritional deprivation.

Physiology Of Cortisol Metabolism

Cortisol Metabolism Hsd

Pathways of Cortisol Metabolism The principal metabolites of cortisol are shown in Figure 18.2. The enzymes directly metabolizing cor tisol include the A-ring reductases (5a- and 5P-reductases), 6 -hydroxylase, 20-reductase, and 11 -hydroxysteroid dehydrogenases. In rats and mice, which lack 17-hydroxylase in their adrenal cortex, the principal glucocorticoid is corticosterone, which is subject to analogous metabolism. 11 P-Hydroxysteroid Dehydrogenases (1ip-HSDs) These enzymes catalyse the interconversion of cortisol (or corticosterone) with its inactive metabolite cortisone (or 11-dehydrocorticosterone) (6). Two isozymes have been cloned (7-10) and their characteristics are shown in Table 18.1. 11P-HSD type 2 is a high affinity (low nM Km for cortisol), NAD-dependent dehydrogenase which rapidly converts cortisol to cortisone. Although expressed in many tissues during fetal life (11-14) including the placenta (10,15,16), in adults it is expressed principally in tissues where...

Leptin Stimulates Production of Anorexigenic Peptide Hormones

Arcuate Nucleus Pathway

The amount of leptin released by adipose tissue depends on both the number and the size of adipocytes. When weight loss decreases the mass of lipid tissue, lep-tin levels in the blood decrease, the production of NPY is diminished, and the processes in adipose tissue shown in Figure 23-32 are reversed. Uncoupling is diminished, FIGURE 23-33 Hormones that control eating. In the arcuate nucleus, two sets of neurosecretory cells receive hormonal input and relay neuronal signals to the cells of muscle, adipose tissue, and liver. Leptin and insulin are released from adipose tissue and pancreas, respectively, in proportion to the mass of body fat. The two hormones act on anorexigenic neurosecretory cells (red) to trigger release of a-MSH this produces neuronal signals to eat less and metabolize more fuel. Leptin and insulin also act on orexigenic neurosecretory cells (green) FIGURE 23-33 Hormones that control eating. In the arcuate nucleus, two sets of neurosecretory cells receive hormonal...

Pathology Of Cortisol Metabolism

Much of what we have learnt of the physiology of cortisol metabolism has been inferred from observations of the consequences of pathology. In this section, we review these pathological clinical syndromes and experimental models. Measurement of Cortisol Metabolism in Humans The established technique for assessing different routes of cortisol metabolism in humans is to measure the principal metabolites of cortisol in urine, using gas chromatography-mass spectrometry (GCMS) (120,121). Examples of major enzyme defects and associated changes in ratios of metabolites are given below. However, these ratios must be interpreted with caution, since they reflect only relative excretion and not flux or turnover through different metabolic pathways. For example, the ratio of the principal metabolites of cortisol cortisone, i.e. (5a- + 5 - is elevated if 11 -HSD2 is congenitally deficient (66) or inhibited by liquorice (63). However, in theory this could also result from a primary increase in 11...

Hypogonadotropic Hypogonadism Associated With Leptin and LeptinR Mutations

The adipocyte-specific hormone, leptin, the product of the obese (ob) gene, acts on the hypothalamus to control appetite and energy expenditure (102). Leptin acts through the leptin receptor (leptin-R), a single transmembrane-domain receptor of the cytokine-receptor family (103). In 1997, Montague reported the first consanguineous family with two very obese prepubertal children who had congenital leptin deficiency (104). The two cousins were homozygous for a frameshift mutation in the leptin gene. Leptin administration to one of these children led to a sustained reduction of weight mainly because of suppressed food intake. Moreover, the patient's basal and stimulated gonadotropin levels increased after 1 yr of leptin therapy and a nocturnal LH secretion pattern was observed, characteristic of midpuberty (105). These findings might suggest a permissive role of leptin in the onset of puberty. In 1998, another consanguineous family with three affected obese individuals who had...

Leptin Triggers a Signaling Cascade That Regulates Gene Expression

Plasma Membrane Leptin Receptor Monomer

The leptin signal is transduced by a mechanism also used by receptors for interferon and growth factors, the JAK-STAT system (Fig. 23-34 see Fig. 12-9). The lep-tin receptor, which has a single transmembrane segment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phos-phorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The -Tyr residues become docking sites for three proteins that are signal transducers and activators of transcription (STATs 3, 5, and 6, sometimes called fat-STATS). The docked STATs are then phosphorylated on Tyr residues by the Leptin receptor monomer Leptin receptor monomer

Altered Cortisol Metabolism In Obesity

Cortisol Metabolism in Primary Obesity Relatively small case-control studies, almost exclusively in women, showed that obesity, particularly of predominantly abdominal distribution, is associated with increased urinary free cortisol excretion (160-162). However, as detailed above, urinary free cortisol forms a very small fraction of total cortisol metabolite excretion. More convicingly, recent large studies confirm that total cortisol production rate is somewhat enhanced in obesity in men as well as women (131,163,164). This is further supported by evidence of enhanced responsiveness of the hy-pothalamic-pituitary-adrenal axis to ACTH and CRH (161,165). However, in obesity plasma cortisol levels are not consistently elevated. Indeed, peak plasma cortisol levels in the morning are low (166-169). The combination of increased secretion with low morning plasma levels suggests either that diurnal variation of cortisol secretion is disrupted, or that peripheral metabolism of cortisol is...

Leptin Deficiency And Appetite Control

It seems clear that for the majority of obese people, the OB protein (leptin) system is not a major cause of rapid or massive weight gain. However, for certain individuals very low levels of leptin (or the absence of leptin) may constitute a major risk factor. Recently a number of individuals have come to light. For example, two young cousins have been studied who displayed marked hyper-phagia from a very early age. This hyperphagia took the form of a constant hunger accompanied by food cravings and a continuous demand for food (17). The eldest of the two cousins had reached a body weight of more than 90 kg by the age of 9. Her serum leptin level (like that of the cousin) was very low, and subsequently a mutation in the gene for leptin was revealed. This finding seems to implicate leptin (OB protein) in the control of the drive for food that is, in the expression of hunger and active food seeking rather than with satiety or the short-term inhibition over eating. Leptin therefore...

Leptin

Studies with rodents have demonstrated that leptin induces lipolysis both in vitro 373, 374 and in vivo 375 . The effect was absent in animals lacking a functional leptin receptor, i.e. db db mice 374, 375 and in Zucker rats 373 . Intriguingly, FA release does not accompany glycerol release in leptin-induced lipolysis, which suggests simultaneous induction of FA oxidation 369 . In these studies, effects on HSL expression were not investigated. Thus it is not known whether the lipolytic effect of leptin is mediated via phosphorylation-induced activation of HSL, an induction of HSL expression, a combination of both, or some other mechanism. In another study, however, long-term treatment of mice with leptin increased HSL mRNA expression by 30 in WAT, whereas no effect was seen in brown adipose tissue 376 . The leptin signal is presumably transduced via the JAK STAT pathway. Leptin was also shown to directly activate the TAG FA substrate cycle, lipolysis and FA oxidation, shifting fuel...

Diagnosis And Tumor Localization

Once there is clinical suspicion of CS, the first step is the biochemical documentation of endogenous hypercortisolism (7,14). This step can usually be accomplished by outpatient tests. Measurement of 24-h urinary-free cortisol (UFC) and or 17-hydroxysteroid excretion and the 1-mg overnight dexamethasone suppression test are frequently employed as the first step. Contemporary diagnostic assays (e.g., immunoradiometric plasma ACTH concentrations before and after CRH) and imaging modalities (high-resolution magnetic resonance imaging MRI ) have dramatically improved the diagnosis of ACTH-dependent CS.

Suggested Reading

Brain and language A perspective from sign language. Neuron 1998,21 275-278. Cooke B, Hegstrom CD, Villenueve LS, Breedlove SM. Sexual differentiation of the vertebrate brain Principles and mechanisms. Front Neuroendocr 1998,19 323-362. Dijk D-J, Duffy JF. Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics. Ann Med 1999,31 130-140. Elmquist JK, Elias CF, Saper CB. From lesions to leptin Hypothalamic control of food intake and body weight. Neuron 1999,22 221-232. Gazzaniga MS. The split brain revisited.

Identifying The Responsible Cellular Event

Insulin resistance is also frequently observed in clinical conditions associated with overproduction of counter-regulatory hormones such as cortisol, epi- nephrine, and growth hormone (6). Specifically, acromegaly, Cushing's syn- drome, and pheochromocytoma, on clinical grounds, are associated with attenuated insulin action and may present with impaired carbohydrate metabolism. A number of other human diseases and conditions characterized by insulin M resistance have been described, as recently reviewed by Hunter and Garvey these J are listed in Table 1 (6).

Radiotherapy see also Chapter

Radiation delivery can also be achieved by high-voltage cobalt-60 particle irradiation, heavy particle beam radiotherapy, and stereotactic radiosurgery. Primary radiotherapy results in CD remission in up to 85 of patients (105,106). Hypercortisolism in these patients may persist up to 3 yr after radiation before a decline to normal cortisol levels can be seen. Radiation in association with mitotane therapy (o-p 'DDD), can produce a remission rate of approx 80 in the first year (107). This can increase further in the second year, but the sustained remission rate after discontinuing mitotane therapy drops significantly to less than 60 of the patients. Mitotane can be discontinued after 1 yr, if UFC has normalized. It can be reinitiated if hypercortisolemia recurs. By 3 yr, 80 to 90 of patients will have achieved biochemical remission of CS and will no longer need mitotane, because the effects of irradiation become established. If mitotane therapy is not tolerated by or fails to cure the...

Corticosteroid Replacement

Glucocorticoid replacement should be started after a successful pituitary adenomectomy (approx on d 5 after low or undetectable serum and urinary cortisol levels have been obtained). The action is undertaken because in those patients the HPA axis is suppressed by the chronic exposure to excess glucocor-ticoids and fails to function for several months after the removal of normal corticotroph inhibition, such as an ACTH-secreting pituitary adenoma (128). Hydrocortisone should be replaced at a rate of 12 to 15 mg m2 d by mouth, with appropriate increases in minor stress (two-fold) and major stress (up to 10-fold) for appropriate lengths of time. The recovery of the suppressed HPA axis can be monitored with a short ACTH test every 3 mo. When the 30-min plasma cortisol exceeds 18 g dl, hydrocortisone can be discontinued. After a bilateral adrenalectomy, corticosteroid replacement will be necessary for life and includes both glucocorticoids and mineralocorticoids.

Figure 31 Relationship between histamine Ht receptor affinity and adjusted weight gain among antipsychotics

Another mechanism by which novel antipsychotics may have an impact on weight is via effects on peptide hormones. Leptin is a hormone produced by adipose tissue that is thought to signal the size of the pool of adiposity to the brain and thereby decrease feeding behavior. In humans, circulating leptin correlates closely with BMI (Kraus et al. 1999). Mice and humans deficient in leptin are obese, whereas parenteral administration of exogenous leptin reverses the abnormalities in food intake and weight in leptin-deficient individuals (Pelleymounter et al. 1995). An early paper examining clozapine-treated patients found increases in both adipose tissue and circulating levels of leptin (Bromel et al. 1998). In a subsequent study which found that leptin was increased in patients treated with clozapine or olanzapine but not with haloperidol, the investigators speculated that the normal hormonal feedback mechanism was impaired in patients taking those novel antipsychotic medications (i.e.,...

Colocalization Of Neurochemicals In Hcrt Neurons

Neurotransmitter receptors that have been reported to colocalize in Hcrt neurons include the GABAa receptor epsilon subunit,33 the pancreatic polypeptide Y4 receptor,34 and the adenosine A1 receptor.35 In addition, the receptor for the adipose hormone leptin is found in Hcrt neurons.23 The significance of these colocalizations will be discussed in Chapter 7 on afferent innervation of Hcrt neurons. Other cellular factors reported to be expressed in Hcrt neurons includes precursor-protein convertase36, secretogranin II,27,37 the transcription factor Stat-3,23,38 and the neuronal pentraxin Narp, implicated in clustering of ionotropic glutamate receptors.39

Hormones Controlling Growth Development and Metabolism

Steroid hormones, also produced in the adrenal glands, stimulate the production of glucose from noncarbohydrate molecules (gluconeogenesis). The stimulus for this is prolonged stress, for example, starvation. These glucocorticoids, such as cortisol and corticosterone, evolved early and are very important in combating stresses resulting from migration among birds and even fish. The pancreatic hormones insulin and glucagon also effect energy metabolism. These two proteins regulate blood sugar, fat, and protein levels. After eating, insulin stimulates transport of these molecules into liver, fat, and muscle cells and then stimulates the incorporation of the simple molecules, such as glucose, amino acids, and fatty acids, into larger storage molecules, such as glycogen, protein, and fats. Glucagon has opposite actions. After a prolonged period without food intake, glucagon stimulates breakdown of complex molecules, such as glyco-gen and fats, into simple...

Lipoprotein Metabolism

Chylomicrons are assembled in the enterocytes of the small intestine after ingestion of dietary fat (triglyceride) and cholesterol. In the lymph and the blood, chylomicrons acquire several apolipoproteins, including apo C-II, apo C-III, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons interact with the enzyme lipoprotein lipase (LPL), which is activated by apo C-II, and the chylomicron core triglyceride is hydrolyzed. The lipolytic products, free fatty acids, can be taken up by fat cells where they are converted back into triglyceride, or by muscle cells, where they can be used for energy. Apo C-III can inhibit lipolysis, and the balance of apo C-II and apo C-III determines, in part, the efficiency with which LPL hydrolyzes chylomicron triglyceride. The product of this lipolytic process is the chylomicron remnant, which has only about 25 of the original chylomicron triglyceride remaining. Importantly, the chylomicron remnants are relatively enriched in...

An Example of an Organ The Skin

The skin is nourished by blood vessels within the dermis. In addition to blood vessels, the dermis contains wandering white blood cells and other types of cells that protect against invading disease-causing organisms. It also contains nerve fibers and fat cells however, most of the fat cells are grouped together to form the hypodermis (a layer beneath the dermis). Although fat cells are a type of connective tissue, masses of fat deposits throughout the body such as subcutaneous fat are referred to as adipose tissue.

Perioperative Medications

To give prophylactic hydrocortisone cover to all patients. This is a safe policy, but in selective adenomectomy hydrocortisone is unnecessary so long as the HPA axis is normal. Hout et al. studied 82 patients with microadenomectomy with a normal HPA axis (2). Only two patients showed evidence of HPA insufficiency in the postoperative period, in whom it was clinically evident and replacement was given safely. Our policy is to administer 100 mg of hydrocortisone on induction only to patients with evidence of cortisol insufficiency.

Presentation and Diagnosis

The symptoms and signs of CAH depend on the degree of enzyme deficiency. For 21-hydroxylase deficiency, this results in a broad clinical picture complete 21-hydrox-ylase deficiency leads to cortisol and aldosterone absence and salt-wasting crisis in the newborn period. The androgen excess results in prenatal virilization of the external genitalia in women (classic salt-wasting form). Less severe 21-hydroxylase deficiency results in milder cortisol deficiency and milder prenatal androgen excess, with prenatal virilization in women, but no aldosterone deficiency (classic simple virilizing form). Patients with the mildest forms present with symptoms caused by androgen excess only pseudo precocious puberty, hirsutism, menstrual irregularities and infertility, all of which are most readily detected in women (nonclassic form) (1).

Steroid Hormones Carry Messages between Tissues

Steroids are oxidized derivatives of sterols they have the sterol nucleus but lack the alkyl chain attached to ring D of cholesterol, and they are more polar than cholesterol. Steroid hormones move through the bloodstream (on protein carriers) from their site of production to target tissues, where they enter cells, bind to highly specific receptor proteins in the nucleus, and trigger changes in gene expression and metabolism. Because hormones have very high affinity for their receptors, very low concentrations of hormones (nanomolar or less) are sufficient to produce responses in target tissues. The major groups of steroid hormones are the male and female sex hormones and the hormones produced by the adrenal cortex, cortisol and aldosterone (Fig. 10-19). Prednisone and prednisolone are steroid drugs with potent antiinflammatory activities, mediated in part by the inhibition of arachidonate release by phospholi-pase A2 (Fig. 10-18) and consequent inhibition of the

Lymphoid Cells and Organs Evolutionary Comparisons

Myeloid Stem Cell Development

In bone marrow, hematopoietic cells grow and mature on a meshwork of stromal cells, which are nonhematopoietic cells that support the growth and differentiation of hema-topoietic cells. Stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages. Stromal cells influence the differentiation of hematopoietic stem cells by providing a hematopoietic-inducing microenvironment (HIM) consisting of a cellular matrix and factors that promote growth and differentiation. Many of these hematopoietic growth factors are soluble agents that arrive at their target cells by diffusion, others are membrane-bound molecules on the surface of stromal cells that require cell-to-cell contact between the responding cells and the stromal cells. During infection, hematopoiesis is stimulated by the production of hematopoietic growth factors by activated macrophages and T cells.

The Fightor Flight Response Is a Result of Widespread Sympathetic Activation

Sympathetic stimulation of the heart and blood vessels results in a rise in blood pressure because of increased cardiac output and increased total peripheral resistance. There is also a redistribution of the blood flow so that the muscles and heart receive more blood, while the splanchnic territory and the skin receive less. The need for an increased exchange of blood gases is met by acceleration of the respiratory rate and dilation of the bronchiolar tree. The volume of salivary secretion is reduced but the relative proportion of mucus increases, permitting lubrication of the mouth despite increased ventilation. The potential demand for an enhanced supply of metabolic substrates, like glucose and fatty acids, is met by the actions of the sympathetic nerves and circulating epinephrine on hepato-cytes and adipose cells. Glycogenolysis mobilizes stored liver glycogen, increasing plasma levels of glucose. Lipol-ysis in fat cells converts stored triglycerides to free fatty acids that...

Mechanisms Of Counterregulatory Failure

In blood glucose (White et al., 1985) (Figure 6.10). Thus, patients with type 1 diabetes of long duration are at risk of severe and prolonged neuroglycopenia during hypoglycaemia as a direct consequence of inadequate glucose counterregulation. Although attenuated growth hormone and cortisol responses are less common, they are late manifestations in terms of diabetes duration. The systemic mediator theory suggests that a substance is released in response to hypogly-caemia which attenuates subsequent sympathoadrenal responses to further episodes of hypo-glycaemia. The initial candidate for this was cortisol, based on two observations first, the attenuating effect of antecedent hypoglycaemia on later sympathoadrenal responses is absent in patients with primary adrenocortical failure and second, in healthy volunteers, following infusions of cortisol (to supraphysiological levels) during euglycaemia, adrenomedullary epinephrine secretion and muscle sympathetic neural activity were reduced...

Physiopathology of Hypogonadism

The majority of nonfunctional tumors are inefficiently secreting rather than nonse-creting. They usually synthesize and immunostain for FSH and or LH and or free a-subunits and P-subunits. The gonadal dysfunction in males with NFPA is primarily related to intrasellar expansion of the tumor with compression of residual glandular tissue (31). In fact, NFPAs usually are macroadenomas, causing hypopituitarism by both direct compression of the portal vessels that limits delivery of hypothalamic releasing factors and focal ischemic necrosis of the normal pituitary tissue. LH secretion is impaired in approx 53 of NFPAs (78,81,82). However, disruption of ACTH, thyroid-stimulating hormone (TSH), and GH secretion may further inhibit gonadal function. In fact, corticotropin releasing factor (CRF) ACTH cortisol, thyroid hormones, and GH IGF-1 modulate spermatogenesis and steroidogenesis.

What Are The Risks Of Heart Bypass Surgery

Depending on the patient, around 2 risk of death. In some, it may be higher, particularly the elderly if they are having other heart procedures, for example, a valve replacement too. The risks are higher in patients who have had a heart attack within two months this is why the operation should be postponed if possible. A freshly damaged heart muscle is soft and electrically irritable and may tear and go into dangerous rhythms. The risk of heart bypass increases in older patients, those with lung, kidney, or liver damage. The risks of stroke are higher in the elderly and in those who have narrowing in their neck or brain arteries, or who have fat deposits in their aorta, or a calcified, hard aorta.

Clinical Implications

Even if the combination of exercise and low fat diet can induce a considerable body energy deficit under free-living conditions, it is likely that adipose tissue-related regulatory factors of energy and fat balance will over time favor the restabilization of body weight. These factors, which are associated with resistance to further loss of weight in the reduced-obese individual, are probably the same ones that promote the achievement of a new body weight plateau in the context of overfeeding. Thus, as discussed above, the decrease in sympathetic nervous system activity and in plasma FFA, leptin, and insulin probably contributes to resistance to losing more fat after having experienced success with exercise and a low fat diet. In this context of increased

Regulation of Transcription by Steroid Hormones

Steroid hormones (estrogen, progesterone, and cortisol, for example), too hydrophobic to dissolve readily in the blood, are carried on specific carrier proteins from their point of release to their target tissues. In target cells, these hormones pass through the plasma membranes by simple diffusion and bind to specific receptor proteins in the nucleus (Fig. 12-40). Hormone binding triggers changes in the conformation of the receptor proteins so that they become capable of interacting with specific regulatory sequences in DNA called hormone response elements (HREs), thus altering gene expression (see Fig. 28-31). The bound receptor-hormone complex can either enhance or suppress the expression of specific genes adjacent to HREs. Hours or days are required for these regulators to have their full effect the time required for the changes in RNA synthesis and

Relationship Between Obesity And Type 2 Diabetes Mellitus

Is prevented by calorie restriction with the prevention of obesity, and the normalization of leptin levels could potentially be advantageous, although this is speculative at this point. Leptin administration. The administration of leptin to either rodents or to humans with leptin deficiency has been shown to reverse this form of obesity (108). The leptin-deficient obese subjects lost significant adipose tissue mass, and reproductive function was restored (108). When administered to non-human primates without any abnormality in the leptin axis, peripheral leptin had no effect on food intake or body weight (109). However, when leptin was administered to the normal monkeys intracerebroventricularly there appeared to be a delayed reduction in food intake the next day. Leptin administered to the obese Psammomys obesus sand rat failed to affect body weight, body fat, or adipose gene expression (110), although there were some gene expression changes induced by leptin in lean control animals....

Lipids and the treatment of cancer

Cancer causes death through a number of mechanisms including direct invasion of critical organs. However, a common and life-threatening feature of many cancers is a marked loss of body fat, cachexia. There have been many investigations of the cause of cancer cachexia. One theory is that a circulating factor, known as cachectin, leads to inhibition of adipose tissue lipoprotein lipase and consequent failure of fat storage (so there is continuous net fat loss). Cachectin is now known to be identical to tumour necrosis factor-a, a cytokine produced by many cell types including macrophages and adipocytes. The evidence for this mechanism has largely been based on animal studies. In humans, measurements of energy intake have shown that the loss of body fat is mainly a problem of energy balance. Patients lose appetite and in many cases involving cancers of the gastrointestinal tract have difficulty eating. There have been some interesting developments in the treatment of cancer cachexia by...

Psychosocial Factors That Influence Coronary Artery Atherosclerosis And Chd Risk In Female Monkeys

Physiological characteristics of subordinates that distinguish them from dominants include differences in measurements of adrenal function. Following dexamethasone suppression, the adrenal glands of subordinate females hypersecrete cortisol in response to an adrenocorticotropic hormone challenge, and are also relatively insensitive to cortisol negative feedback (15). Since the hypersecretion of cortisol is typically viewed as indicative of a stressed individual, these findings imply that, in general, subordinate females are stressed females. Current subordinates hypersecreted cortisol, were insensitive to negative feedback, and had suppressed reproductive function. Current subordinates received more aggression, engaged in less affiliation, and spent more time alone than dominants. Furthermore, they spent more time fearfully scanning the social environment and displayed more behavioral depression than dominants. Current subordinates with a history of social subordination were...

The Coordination Of Lipid Metabolism In The Body

Several genes involved in lipid metabolism are themselves regulated by lipid or lipid-related molecules, and adipose tissue itself secretes proteins that regulate food intake and fat storage. There are three known isoforms of SREBP SREBP-1a, SREBP-1c and SREBP-2. The first two arise from differential splicing of the transcript from one gene, whereas SREBP-2 is the product of a separate gene. It seems that SREBP-1a and 1c are concerned more with regulation of genes involved in fatty acid metabolism including fatty acid syn-thase, acetyl-CoA carboxylase and stearoyl-CoA (A9) desaturase (Section 2.2.8), whereas SREBP-2 regulates transcription of genes involved in cholesterol metabolism (Section 7.5.7). SREBP-1c is also expressed in adipose tissue (where it is also known as adipocyte determination and differentiation factor-1, ADD-1), and has been shown to regulate fatty acid synthesis by increasing the expression of fatty acid synthase in adipose tissue as well as liver. Leptin...

Obesity Perinatal Factors

Subjects with the small baby syndrome and abdominal preponderance of body fat stores have recently been reported to have elevated cortisol secretion (26). This might correspond to the group of men we have studied with elevated stress-related cortisol and centralization of body fat (8,17). There are experimental studies which indicate potential mechanisms. The HPA axis can be sensitized by intrauterine exposure to immune stress or cytokine exposure or to lipopolysaccharides (27,28), and the handling of newborns has also been shown to be of importance (29). Recent studies have provided further interesting information, probably explaining the effects of prenatal exposure to lipo-polysaccharides. These bacterial endotoxins stimulate the secretion of cytokines. Prenatal exposure to interleukin-6, tumour necrosis factor a or dex-amethasone, a synthetic glucocorticoid which passes the placental barrier, is followed by permanent sensitization of the HPA axis, leptin-resistant obesity and...

Regulating Other Functions

Further endocrine glands include the adrenal cortex, located on top of each kidney, which secretes three major classes of steroid hormones the glucocorticoids such as cortisol, which controls fat and protein metabolism the mineralocorticoids such as aldosterone, which controls blood sodium levels and the androgens (male sex steroids). The

Clinical Focus Box 241

Hyponatremia with hypoosmolality can occur in the presence of a decreased, normal, or even increased total body Na+. Hyponatremia and decreased body Na+ content may be seen with increased Na+ loss, such as with vomiting, diarrhea, and diuretic therapy. In these instances, the decrease in ECF volume stimulates thirst and AVP release. More water is ingested, but the kidneys form osmotically concentrated urine and plasma hypoosmolality and hyponatremia result. Hyponatremia and a normal body Na+ content are seen in hypothyroidism, cortisol deficiency, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH occurs with neurological disease, severe pain, certain drugs (such as hypoglycemic agents), and with some tumors. For example, a bronchogenic tumor may secrete AVP without control by plasma osmolality. The result is renal conservation of water. Hyponatremia and increased total body Na+ are seen in edematous states, such as congestive heart failure, hepatic...

Generalized Tonic ClonicSeizures

Abbott and coworkers (21) demonstrated elevations of serum prolactin and cortisol following spontaneous GTCS, but only serum Cortisol responded to simulated convulsive seizures. Abbott considered Cortisol a nonspecific response to stress, contrasted with a specific seizure-induced rise in PRL.

We Need Some Cholesterol In Our Blood But Not Too Much

The main one causing blockages in the arteries is cholesterol. Although it causes problems when it gets deposited in the walls of the arteries, we cannot live without it. It has three main roles. It is an essential part of our cell walls, it is one of the chemicals used to make sex hormones (e.g., testosterone) and other steroid-containing hormones like cortisol, and it is also a component of bile acids, which are made in the liver and allow us to digest and absorb fats from the diet.

Cushings Disease Acthsecreting Pituitary Adenoma

Endogenous glucocorticoid excess (Cushing's syndrome CS ) most commonly results from an ACTH-producing pituitary adenoma. The majority are small microadenomas, and are difficult to define on magnetic resonance imaging (MRI) imaging the mean size of an ACTH-secreting pituitary adenoma is 6 mm. Adenomectomy is the treatment of choice to control Cushing's disease (CD), and it is recommended that surgery be performed by a specialist surgeon. In this setting, approx 90 of patients with CD will undergo successful cure, i.e., a lowering of cortisol production to within the normal range (18). However, this figure falls to 50-65 (in three recent British audits Oxford, Newcastle, and the National Hospital, London) if cure implies removal of all tumor tissue such that the residual cortisol from the normal corticotrophs is suppressed to below the detectable range. Removal of the ACTH-secreting adenoma results in an immediate reduction in circulating ACTH levels, with consequent lowering of serum...

Long Term Management of Patients After Successful Pituitary Surgery for Cushings Disease

Many patients will have undetectable (< 50 nmol L or 1.8 Mg dL) early morning cortisol concentrations after pituitary surgery. Once cure has been established, replacement glucocorticoids should be initiated and titrated to ensure satisfactory clinical response and biochemical levels. Many centers favor the use of hydrocortisone or cortisone acetate, facilitating measurement of cortisol concentrations to monitor therapy. Most patients receive divided doses, typically three times a day, taken before rising in the morning, at midday and in the early evening, allowing for circadian dynamics close to those seen in the healthy population. A hydrocortisone day curve (HCDC) allows measurement of this pattern (see Endocrine Protocols, Appendix 1, p. 201). All patients should receive a steroid card and instruction on management of glucocorticoid replacement during periods of illness, while specialist centers may also provide an emergency pack for parenteral (usually intramuscular)...

Other Potential Causes of Androgen Deficiency

Men with pre-existing testicular dysfunction (including renal failure) may be more susceptible to further impairment of steroidogenesis caused by medications or illnesses. HMG-CoA reductase inhibitors inhibit cholesterol synthesis and may, therefore, impair steroidogenesis, particularly because adverse events consistent with androgen deficiency (gynecomastia and impotence) have been reported. A prospective, open-label study of 25 nephrotic, hyperlipidemic men with moderate chronic renal failure treated for 12 mo with lovastatin (40 mg d) showed no change in baseline and GnRH-stimulated LH, FSH, and testosterone levels (38). A more discerning test of testicular steroidogenesis, such as testosterone response to submaximal hCG stimulation, was not reported. Adrenal steroidogenesis (plasma cortisol before and after adrenocor-ticotropic hormone ACTH stimulation) was comparable with age-matched healthy controls at entry and remained unchanged by lovastatin treatment. Not surprisingly,...

Use Of Serum Prolactin As A Diagnostic Tool In Epilepsy Practice And Pitfalls

NES produces increases in serum cortisol levels, but most studies have demonstrated no effect on PRL. Thus, a generalized convulsive event that does not produce a rise in serum PRL almost always represents a nonepileptic event. A rise in PRL after a staring spell, which potentially represents an absence, complex partial, or psychogenic nonepileptic seizure, almost certainly reflects a CPS.

Estrogens And Other Hormone Derivatives

In postmenopausal women, several studies (93,94) have also demonstrated that hormone replacement therapy if anything may lead to a small weight reduction. This effect is not fully understood, but increased lipid oxidation seems to be of importance, whereas circulating leptin is not affected (95,96).

Summary And Conclusions

Weight gain associated with tricyclic antidepress-ant and certain antipsychotic medications is problematic for many treated patients, and often a reason for non-compliance. Such weight gain is associated, at least in part, with reductions in resting metabolic rate and diet-induced thermogenesis. Changes in food preference towards calorically dense ('fattening') sweet-tasting foods do not appear to affect a majority of patients treated with tricyclic medications, but can occur. When such preference changes do occur, though, they are not associated with the development or maintenance of obesity. Another class of antidepressants, specific serotonin reuptake inhibitors (SSRIs), have been used in the past few years as effective antidepressants, but do not promote weight gain during treatment, although this is occasionally seen. The antipsychotic medications often promote weight gain, particularly the conventional medications, but also some of the novel antipsychotics seem to have weight...

Orexigenic and Anorexigenic Studies

A combination of central and peripheral mechanisms control food intake. Indeed, hypothalamic nuclei and the brainstem act as input stations for hormonal and gastrointestinal information (10,11). Furthermore, peripheral satiety factors such as cholecystokinin (CCK) activate CCK1 receptors on vagal afferents, which transmit signals to hindbrain nuclei such as the nucleus tractus soli-tarius (NTS). The NTS in turn communicates with several hypothalamic nuclei, which play critical roles in appetite regulation. In addition, adipose tissue secretes the hormone leptin, which enters the CNS and stimulates the arcuate nucleus within the hypothalamus. Leptin appears to be the main signal via which the hypothalamus senses nutritional states and modulates food intake. Leptin directly affects neurons in which either the anorexigenic (appetite-reducing) peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) or the orexigenic (appetite-stimulating) peptides...

Social Characteristics

Sex refers to the ascribed biological status of being female or male (as differentiated by anatomy and physiology), while gender refers to the achieved social status of being a woman or man (as constructed by psychosociocultural factors). Clear sexual dimorphism exists in body weight, with females generally having more stored body fat than males and being more likely than males to be obese (5,34). Many sex differences are physiological and linked to reproductive functioning (50), with more overall subcutaneous fat present in females and the distribution of body fat deposits being greater in lower body for females and upper body for males.

Genetic influences on the metabolic syndrome

It has long been thought that obesity precedes the metabolic syndrome, but it is now known that this syndrome can be observed in lean subjects, even if its prevalence increases in a graded fashion as body weight increases (St-Onge et al., 2004). Recent findings about the endocrine (but also paracrine and autocrine) function of adipocytes have renewed interest in the topic. Indeed, it has been demonstrated that fat cells are able to secrete pro-inflammatory and insulin resistance-inducing cytokines (TNF-alpha, resistin), as well as molecules acting in concert to facilitate glucose uptake (adiponectin) or the central control of satiety (leptin) (Lafontan, 2005). Accordingly, candidate genes for predisposition to the metabolic syndrome are those involved in the fat cell metabolism, including secreted adipokines, or the insulin signalling pathway acting in liver, muscle or fat cells. Some of them have already been described above, those associated with dyslipidaemia (Laakso, 2004), such...

Lowdose Dexamethasone Suppression Test

Serum cortisol should be measured in all cases. In healthy individuals, the basal 09.00 h serum cortisol ranges between 170 and 700 nmol L (6-25 g dL). Following dexamethasone the 48 hour sample should be < 50 nmol L (1.8 g dL). Reasons for failure of suppression include Cushing's syndrome, noncompliance, glucocorticoid resistance, alcoholic pseudo-Cushing's, severe physical or psychiatric illness, and hepatic enzyme induction. Elevated cortisol-binding globulin as occurs in hyperestrogenemic states, such as pregnancy or in those taking the combined oral contraceptive pill, may result in elevated total cortisol, which fails to suppress.

Dietary fatty acids and the regulation of gene expression

Genes coding for transport and metabolism of FAs. This is a sparing process that is achieved through the binding of acyl-CoA to a specific DNA binding protein that changes its affinity for DNA response elements. In mammals, the expression of genes involved in transport and metabolism appears to be regulated by FAs in a positive or a negative manner. However, the simple bacterial process could provide the paradigm of the regulation of gene expression by FAs. FAs or derivatives depress genes coding for enzymes involved in lipogenesis and activate those that allow the transport and the oxidation of FAs. FA binding to transcription factors modifies their involvement in the transcription process. As a matter of fact, in mammals several genes coding for proteins involved in lipogenesis or weight control such as leptin, are down-regulated. This mechanism may be related to the decrease in hepatic de novo lipogenesis that can be observed in animals and humans submitted to a polyunsaturated...

Methodological Developments

The pattern of ACTH and cortisol variations shows an early morning peak, declining levels during the daytime and minimal secretory activity in the evening. This secretory pattern is brought about by the nervous system. There is, however, no sharp distinction between the endocrine and nervous systems, and in the hypothalamus and the pituitary there is a close connection between these two systems that integrates the two into one control unit. The CRH-secreting neurons, located within the paraventricular nuclei (PVN) (18), receive afferent regulatory signals from different parts of the brain. Stimulatory inputs arise from the suprachiasmatic nucleus (the regulator of circadian rhythms), the amygdala and the raphe nuclei (19,20), while inhibitory inputs on CRH secretion arise in the hippocampus and in the locus coeruleus. The CRH In summary, the central nervous system provides inputs in terms of registrations by the senses, modified by experience and coping ability, and the integrated...

Methodological Comparisons

The concentration of cortisol in saliva, although approximately 30-50 lower (34), correlates closely with the concentration of free cortisol in serum (r x 0.90). Consequently, salivary cortisol measurements are an excellent index of the total, free cortisol concentration in serum as well as in urine in both normal and pathological conditions (27-30). Cortisol has effects at nearly all levels in the human body, including an important role in lipid and glucose metabolism. Cortisol also inhibits most inflammatory processes (35), increases the left ventricular work index (36), and increases glomerular filtration rate, renal blood flow and potassium and acid excretion (37,38). Centralization of body fat is most likely an effect of cortisol, as clearly seen in Cushing's syndrome, exhibited as severe truncal obesity. After successful therapy, the somatic features of Cushing's syndrome disappear (39). This provides evidence that cortisol may have a most potent stimulatory effect on central,...

Subgrouping Of Visceral Obesity With The Metabolic Syndrome

Visceral obesity is associated with other endocrine abnormalities than that of cortisol. Indeed, visceral obese individuals with the metabolic syndrome may have all the hormonal abnormalities of the elderly, suggesting that this condition may be a sign of premature ageing (58). The most common deficiencies are those of growth hormone (GH) and sex steroids (59). Whereas men have low testosterone levels (60), women have irregular menstrual cycles (61). Functionally, the growth axis and the reproductive axis are influenced at many levels by the HPA axis. Prolonged activation of the HPA axis thus leads to suppression of GH secretion as well as inhibition of sex steroids (23,62). These endocrine abnormalities have a profound effect on peripheral tissues. While cortisol promotes accumulation of visceral fat and insulin resistance in muscle tissue, the GH and sex steroids, often in concert, do the opposite (42). Low GH and sex steroid secretions will thereby multiply the pathogenetic effects...

Subgrouping Of The Hpa Axis Perturbations

Throughout recently performed studies (67-70), we have been able to single out subgroups of the functional status of the HPA axis within a general population of non-cushingoid middle-aged men. The first group was characterized by a high morning cortisol peak, a normal circadian rhythm (variability) and feedback regulation (dexamethasone) along Normal High cortisol High Low cortisol Normal Low GH and sex steroids Low cortisol with a brisk cortisol response to lunch. Such men are in general lean, measured as BMI and WHR, with higher values of IGF-I than average, and low total and low density lipoprotein (LDL) cholesterol as well as blood pressure. The other group identified was characterized by the absence of a morning cortisol peak and cir-cadian rhythm, a blunted suppression of cortisol by overnight low dose dexamethasone and a poor lunch-induced cortisol response. Such men suffer from obesity with a predominance of centrally located body fat, low testosterone and IGF-I...

Stages Of The Hpa Axis Functional Status

The above subgroups of the functional status of the HPA axis represent extremes in terms of the resiliency of the HPA axis. Although strongly genetically determined (71), environmental and social factors also affect the circadian rhythm of the HPA axis (72). The question arises whether there are time- and stress-related changes in patterns of HPA axis activity and regulation, and if it is possible to tentatively define stages of such HPA axis affliction. A first stage then would be a normal function of the HPA axis, defined as a normal circadian rhythm with high morning and low afternoon-evening cortisol levels, and normal feedback control of GRs. Total cortisol output is regulated within the normal range and this is associated with optimal health. A second stage is seen upon acute stress where central regulation of HPA axis rhythm is maintained as well as the feedback control. The growth and reproductive axes are not affected. Cortisol secretion will, however, be elevated with...

How May Stress Affect The Heart

High levels of adrenaline and noradrenaline in the blood for long periods increase the blood pressure, and this increases fat deposits in arteries. Sudden increases in these chemicals are thought to inflame the artery wall, causing cracking of the surface layer of the fat. Blood clots form on the cracked fat layer, blocking off the artery, and cause a heart attack.

Environmental Factors Influencing The Hpa Axis

Recently been shown to be associated with elevated stress-related cortisol secretion as well as visceral obesity (95). Moreover, we have identified a subgroup of elevated WHR and D, where a blunted dexamethasone response is found, associated with traits of anxiety and depression as well as personality disorders (57,96). It has been suggested that persistent psychosocial and socioeconomic handicaps constitute a base for stress, resulting in frequent challenges of the HPA axis (43). Although biologically plausible, this hypothesis has been difficult to study in humans. In primates other than humans, a diminished feedback regulation of the cortisol secretion, suppression of the reproductive axis, and depressive behaviour follow exposure to standardized, moderate psychosocial stress (97,98). Moreover, such social stress is associated with visceral obesity, insulin resistance, dyslipidaemia, hypertension and coronary artery atherosclerosis (97,98). Thus, these results bear a striking...

Indications For Gamma Knife Radiosurgery

Patients with acromegaly, Cushing's disease (CD), Nelson's syndrome, or a prolactinoma unresponsive to dopamine agonist therapy are candidates for pituitary radiation therapy. Although medications may control excessive growth hormone (GH) secretion in patients with acromegaly and excessive cortisol production in patients with CD, no current medical therapy cures the disease. Thus, definitive therapy is necessary, and pituitary radiation offers the possibility of remission or cure. In patients with acromegaly, CD and Nelson's syndrome, the first treatment is usually surgery to remove as much of the tumor as possible. If there is residual disease, then medical therapy is given to control hormone hypersecretion (acromegaly, CD). In patients with a prolactinoma who do not respond to dopamine agonist therapy (approx 8 of patients), additional treatment, which may include surgery and radiation therapy, is indicated. Even though a large invasive tumor cannot be cured with surgery, the...

Assessment Of Response To Gamma Knife Treatment

Because GH production is influenced by age and gender (GH secretion declines with increasing age), it is necessary to have the IGF-1 level measured in a laboratory that provides normal values in relation to age and gender. In patients with CD, the 24-h UFC concentration is the best measure of integrated cortisol production. A normal 24-h UFC is an excellent measure of excessive cortisol production but is not helpful to assess adrenal insufficiency. A single serum PRL measurement in a patient with a prolactinoma is sufficient to assess the response to Gamma Knife therapy. Gonadal function is assessed by a history of normal libido and erectile function and a normal serum testosterone in men. In premenopausal women, regular menses indicate normal ovarian function. Men should have serum testosterone measured regularly, and menstrual history and serum estradiol levels should be measured in premenopausal women. In patients with Nelson's syndrome (increased serum ACTH...

Immunity to infection in pregnancy

The pregnancy-related alteration in the immune response in infection includes changes in T cell subpopulations, neutrophil function, lymphocyte function, serum immunoglobulin concentrations, immunosuppressive serum factors, and maternal immune recognition mechanisms. The decrease in cell-mediated immunity associated with pregnancy, whilst clearly affected by the altered Thj Th2 balance, is also influenced by a number of factors including the steroid hormones progesterone, oestrogen, cortisol, a-feto protein and uromodulin.

Stress and the Sympathetic Nervous System

In the ARIC study, clinical atherosclerosis was associated with low income and low education (313). Also, there was a correlation between cerebrovascular disease and anger and aggression (314). Chronic psychological risk factors (hostility and low socioeconomic factors) are important at early disease stages. Episodic factors (depression and exhaustion) are involved in the transition from stable to unstable atherosclerotic plaques, and acute psychological triggers (mental stress and anger) can promote myocardial ischemia and plaque rupture (reviewed in ref. 315). It has been proposed that postprandial insulin resistance along with increased levels of Cortisol and catecholamines, specifically

Role Of Hypocretin In Sleep Regulation

These metabolic findings and the evidence of involvement of hypocretin in endocrine regulation in animal studies incited additional neuroendocrine studies in human narcolepsy. A study of diurnal rhythms of leptin, hypothalamo-pituitary-adrenal, somatotropic-, gonadal-, and thyroid hormones in hypocretin deficient male narcoleptic patients showed abnormalities in all secretion patterns, the most robust in leptin.

Steroid Hormones Are Derived From Cholesterol

Glucocorticoids, such as cortisol, are primarily produced in cells of the adrenal cortex and regulate processes involved in glucose, protein, and lipid homeostasis. Glucocorticoids generally produce effects that are catabolic in nature. Aldosterone, a primary example of a mineralocorti-coid, is produced in cells of the outermost portion of the adrenal cortex. Aldosterone is primarily involved in regulating sodium and potassium balance by the kidneys and is the principal mineralocorticoid in the body.

Hypocretin And Brain Reward Modulation

The mechanisms underlying food restriction-induced enhancement of central rewarding potency of both lateral hypothalamic self-stimulation and drugs of abuse remain unclear.3133 However, two hormones have been mainly involved in the modulation of the LHSS induced by food restriction, insulin30 and leptin.4276 Notably, intracerebroventricular (ICV) infusion of leptin attenuates the effectiveness of the rewarding electrical stimulation in areas of the LH where previous stimulations were enhanced by chronic food restriction, an effect that persists as long as 4 days after a single injection.42 Interestingly, Hcrt neurons express leptin receptors, and leptin regulates Hcrt neurons.3977 Secondly, neurons containing hypocretin orexin in the LH are activated by insulin-induced acute hypoglycemia.4078 Therefore, it is possible that the hypocretin system mediates both insulin and leptin effects on LHSS, and thus could be considered as the link between the controls of energy homeostasis and the...

Hypocretin And Relapse For Drugseeking

In contrast to Hcrt-1-induced long-lasting elevations in ICSS thresholds, a single injection of Hcrt-1 was associated with a slight effect on cocaine self-administration, given that cocaine consumption remained nearly unchanged just after or 6 hours after the Hcrt-1 infusion.61 Preliminary results obtained in our lab showed that Hcrt did not induce any significant increase on heroin intake in rats either. Furthermore, despite an effect on ICSS thresholds,42 leptin does not modulate cocaine nor heroin self-administration in rats. Such a discrepancy between a marked elevation in ICSS thresholds and an absence of effect on both cocaine and heroin intake remains unclear. However, dissociation of neural systems subserving positive reinforcement and incentive motivation has been proposed previously.83-85 Leptin (2pg n 5)

Vascular effects of et1

ET-1 generation is modulated by shear stress that downregulates its release by endothelial cells (10). NO production, stimulated by shear stress, is an important inhibitor of ET-1 release (11), and may thus be a mediator of this effect. Hypoxia, epinephrine, thrombin, Ang II, vasopressin, cytokines, insulin, and growth factors such as TGF- 1 stimulate endothelial release of ET-1. Leptin has also been shown to upregulate ET-1 production by endothelial cells (12), which could explain in part increases of ET-1 in obesity. This may represent a mechanism that relates obesity to frequently associated cardiovascular conditions including hypertension and atherosclerosis, or that contributes to the evolution of the metabolic syndrome toward type 2 diabetes. Peroxisome proliferator-activated receptors (PPARs) are nuclear factors involved in adipocyte differentiation and insulin sensitivity that have been recently shown to exhibit potent anti-inflammatory and antigrowth properties (13-15). Both...

Hormonal Regulation of Fuel Metabolism

The minute-by-minute adjustments that keep the blood glucose level near 4.5 mm involve the combined actions of insulin, glucagon, epinephrine, and cortisol on metabolic processes in many body tissues, but especially in liver, muscle, and adipose tissue. Insulin signals these tissues that blood glucose is higher than necessary as a result, cells take up excess glucose from the blood and convert it to the storage compounds glycogen and tria-cylglycerol. Glucagon signals that blood glucose is too low, and tissues respond by producing glucose through glycogen breakdown and (in liver) gluconeogenesis and by oxidizing fats to reduce the use of glucose. Epi-nephrine is released into the blood to prepare the muscles, lungs, and heart for a burst of activity. Cortisol mediates the body's response to longer-term stresses. We discuss these hormonal regulations in the context of three normal metabolic states well-fed, fasted, and starving and look at the metabolic consequences of diabetes...

Clinical Focus Box 321

GH is also thought to function as one of the counter-regulatory hormones that limit the actions of insulin on muscle, adipose tissue, and the liver. For example, GH inhibits glucose use by muscle and adipose tissue and increases glucose production by the liver. These effects are opposite those of insulin. Also, GH makes muscle and fat cells resistant to the action of insulin itself. Thus, GH normally has a tonic inhibitory effect on the actions of insulin, much like the glucocorticoid hormones (see Chapter 34).

The View Of The Lh In The Modern Hypothalamus

Genetic and molecular experiments support a role for the hypothalamus in the regulation of feeding and have begun to identify key molecules that control this function. It is believed that the leptin protein, generated in peripheral adipocytes, communicates with the brain in large part through the MH. Current models speculate that information from peripheral signaling molecules, such as leptin, travels from the MH to the paraventricular nucleus and LH in order to enact behavioral responses. Indeed, LH neurons express receptors for a number of neuropeptides made in the MH. However, leptin receptors are also expressed on the LH neurons,1112 raising the possibility that leptin might act directly on LH neurons to cause changes in gene expression1213 and behavior. Interestingly, leptin has been shown to modulate LH-mediated ICSS,14 suggesting that peripheral signals, via direct or indirect pathways, interact with the LH. While the neurocircuitry details are not completely understood, these...

Myocardial Infarction

Only a few cases have been published of myocardial infarction and hypoglycaemia in diabetic patients (Purucker et al., 2000 Chang et al., 2007). This possible association is very difficult to establish because of the problems described above. In addition, the release of stress hormones such as glucagon, cortisol and epinephrine will raise blood glucose and make the contribution of preceding hypoglycaemia almost impossible to confirm.

And Laboratory Investigations

Laboratory investigations show signs of mild liver dysfunction. Serum cortisol level is low, with an increased ACTH value. In serum and fibroblasts, very-long-chain fatty acids (VLCFA) are elevated, but no increase is found in plasma levels of phytanic acid, pristanic acid, pipecolic acid, and bile acids like dihy-droxycholestanoic acid and trihydroxycholestanoic acid. In fibroblasts, VLCFA -oxidation is seriously deficient, whereas de novo plasmalogen biosynthesis and other peroxisomal parameters are normal. The diagnosis is confirmed by measuring the activity of

Clinical Focus Box 341

In primary adrenal insufficiency, all three zones of the adrenal cortex are usually involved. The result is inadequate secretion of glucocorticoids, mineralocorticoids, and androgens. Major symptoms are not usually detected until 90 of the gland has been destroyed. The initial symptoms generally have a gradual onset, with only a partial glucocorticoid deficiency resulting in inadequate cortisol increase in response to stress. Mineralocorticoid deficiency may only appear as a mild postural hypotension. Progression to complete glucocorticoid deficiency results in a decreased sense of well-being and abnormal glucose metabolism. Lack of mineralocorticoid leads to decreased renal potassium secretion and reduced sodium retention, the loss of which results in hypotension and dehydration. The combined lack of glucocorticoid and mineralocorticoid can lead to vascular collapse, shock, and death. Adrenal androgen deficiency is observed in women only (men derive Treatment for acute adrenal...

Future Prospects With Promising Molecules

The discovery of the ob gene and its product leptin (109) has stimulated research in the field of genetics and molecular biology, with rapid advances being made in the understanding of weight-regulating mechanisms. This has led to the identification of a series of potential new targets for the treatment of obesity. However, experience has shown that it is not easy to translate this knowledge into clinically safe and effective pharmacological compounds. An important reason is that results found in laboratory animals are not always reproducible in human subjects. We will focus on a few of these newly identified targets and the corresponding compounds in development, which can be divided into those acting on energy intake and those acting on energy expenditure (110). Appetite and food intake are modulated by several hormones and neurotransmitters acting in a complex interaction. Two major systems can be identified the short-term regulation of food intake...

Mangs Spacelift Introduction

The name spacelift was chosen by the author and protected by patent (no. 30323891) as appropriately purified and centrifugated, recycled fat droplets are injected into the entire face, as in a honeycomb, using microinjections. The fat particles break down but, as a result of the contact with vessels (because they are not injected in large quantities in a bolus dose), they are able to form their own fibroblasts and the catabo-lized fat cells are augmented with fibroblasts and elastin fibers. Virtually no scars are formed and the face stabilizes as a result of the procedure. Naturally, injections can be made beneath other wrinkles in the forehead and nasolabial area using a conventional fat injection technique. Lipo-transfer is also recommended for lip augmentation.

Differences in Regulation of TAG Storage and Mobilization between Visceral and Subcutaneous Adipocytes

Individuals with peripheral obesity possess fat distribution subcutaneously in glu-teofemoral areas and the lower part of the abdomen, and are at little risk of metabolic complications, such as NIDDM. Conversely, individuals with upper-body obesity accumulate fat in subcutaneous and visceral deposits and are more susceptible to metabolic problems, in particular when visceral fat deposits are abundant. Visceral fat deposits, located in the body cavity, are composed of the omental and mesenteric fat, and comprise the minor component of total body fat, representing 20 and 5-8 of total body fat in men and women, respectively. In upper-body obesity, fat excess is present in the visceral abdominal regions but also in the subcutaneous abdominal regions. There are several explanations but no clear proof why upper-body obesity is more at risk of developing metabolic disease than lower-body obesity 499 . Since the visceral deposit is in direct contact with the liver through the portal...

Predictive Indicators Of Cardiogenic Shock

A diagnosis of diabetes mellitus increases the likelihood of cardiogenic shock (3,5,11,12). Notably, the presence of diabetes mellitus did not increase risk in the SPRINT trial, but an admission glucose of > 180 mg was predictive of shock particularly in nondiabetics (1). An enhanced activation of stress-related compensatory mechanisms (release of catecholamines, cortisol, etc.) in patients destined for shock may explain this finding (80). Elevation of blood lactate levels have also preceded the manifestations of cardiogenic shock (81).

Maternal Physiology Changes Throughout Gestation

The thyroid gland enlarges, but TSH levels are in the normal nonpregnant range. T3 and T4 increase, but thyrox-ine-binding globulin (TBG) also increases in response to the rising levels of estrogen, which are known to stimulate TBG synthesis. Therefore, the pregnant woman stays in an euthyroid state. The parathyroid glands and their hormone, PTH, increase mostly during the third trimester. PTH enhances calcium mobilization from maternal bone stores in response to the fetus's growing demands for calcium. The rate of adrenal secretion of mineralocorticoids and glucocorticoids increases, and plasma free cortisol is higher because of its displacement from transcortin, the cortisol-binding globulin, by progesterone, but hypercorti-solism is not apparent during pregnancy. Maternal metabolism responds in several ways to the increasing nutritional demands of the fetus. The major net weight gain of the mother occurs during the first half of gestation, mostly resulting from fat deposition. This...

Endocrine Actions Of Hypocretins

Both aldosterone and corticosterone73 and in vitro studies have reported stimulatory effects of both hypocretins on cortisol secretion.75,117 The relevance of the hypocretin-HPA axis in humans remains unclear. Nevertheless, regulatory actions of hypocretins on pituitary-adrenal axis are supported by data obtained in narcoleptic humans. These patients exhibit normal cortisol levels despite the fact that ACTH secretion is markedly decreased, suggesting alterations in the interaction between the HPA hormones.124,125 In this sense, a recent study in rat has reported that the expression of the enzymes involved in the steroid metabolism is altered during sleep.126 Thus, it is tempting to speculate that changes in the hypocretin tone during sleep could act directly on adrenocortical metabolism, explaining then the lack of association between ACTH and cortisol levels. The physiological relevance of the hypocretin system in reproductive function could be related to the adaptation of the...

Eukaryotic Gene Expression Can Be Regulated by Intercellular and Intracellular Signals

The effects of steroid hormones (and of thyroid and retinoid hormones, which have the same mode of action) provide additional well-studied examples of the modulation of eukaryotic regulatory proteins by direct interaction with molecular signals (see Fig. 12-40). Unlike other types of hormones, steroid hormones do not have to bind to plasma membrane receptors. Instead, they can interact with intracellular receptors that are themselves transcriptional transactivators. Steroid hormones too hydrophobic to dissolve readily in the blood (estrogen, progesterone, and cortisol, for example) travel on specific carrier proteins from their point of release to their target tissues. In the target tissue, the hormone passes through the plasma membrane by simple diffusion and binds to its specific receptor protein in the nucleus. The hormone-receptor complex acts by binding to highly specific DNA sequences called hormone response elements (HREs), thereby altering gene expression. Hormone binding...

Types of Endocrine Disorders

Defects And Hormone

An endocrine gland may be secreting too little hormone because the gland is not able to function normally. This is termed primary hyposecretion. Examples of primary hyposecretion include (1) genetic absence of a steroid-forming enzyme in the adrenal cortex, leading to decreased cortisol secretion, and (2) dietary deficiency of iodine leading to decreased secretion of thyroid hormones. There are many other causes infections, toxic chemicals, and so on all having the common denominator of damaging the endocrine gland. a. The most important steroid hormones produced by the adrenal cortex are the mineralocorticoid aldosterone, the glucocorticoid cortisol, and two androgens. cortisol Diagram the CRH-ACTH-cortisol system. 7. A person is receiving very large doses of a cortisol-like drug to treat her arthritis. What happens to her secretion of cortisol

Chemical Classification of Hormones

Chemical Classes Hormones

These are lipids derived from cholesterol. They include the hormones testosterone, estradiol, progesterone, and cortisol (fig. 11.2). Leptin Cortisol (hydrocortisone) Steroid hormones are secreted by only two endocrine glands the adrenal cortex and the gonads (fig. 11.2). The gonads secrete sex steroids the adrenal cortex secretes corticosteroids (including cortisol and aldosterone) and small amounts of sex steroids.

Semi Synthesis of Corticosteroids

Synthesis Beclometasone Propionate

The medicinal use of corticosteroids was stimulated by reports of the dramatic effects of cortisone on patients suffering from rheumatoid arthritis in the late 1940s and early 1950s. The cortisone employed was isolated from the adrenal glands of cattle, and later was produced semi-synthetically by a laborious process from deoxycholic acid (see page 260) isolated from ox bile and necessitating over 30 chemical steps. Increased demand for cortisone and hydrocortisone (cortisol) (it had been shown that cortisone was reduced in the liver to hydrocortisone as the active agent) led to exploitation of alternative raw materials, particularly plant sterols and saponins. A major difficulty in any semi-synthetic conversion was the need to provide the 11 -hydroxyl group which was essential for glucocorticoid activity. hydrocortisone (Cortisol) hydrocortisone (cortisol) hydrocortisone (cortisol) R1 OH, R2 H, hydrocortisone (Cortisol) R1 OH, R2 H, hydrocortisone (Cortisol) Natural corticosteroid...

Immobilization of Cells With Transition Metal

Sterile solution of 10 g L yeast extract either with or without 0.3 g L cortisol in 20 mM potassium phosphate buffer, pH 7.0. 3. Cortisol (inducer of the steroid A1-dehydrogenase) powder is added to the fermentation medium 8 h after inoculation to a final concentration of 0.3 g L. The determination of biocatalytic activity is based on the A1-dehydrogenation of cortisol to prednisolone. 1. Add 500 mg of immobilized biocatalyst to 5 mL of a 1.0 g L solution of cortisol in -decanol (previously saturated with 20 mM phosphate buffer, pH 7.0), containing 80 mg L of menadione (external electron acceptor see Note 4). 3. Steroid analysis is performed by high performance liquid chromatography (HPLC) using a Lichrosorb Si-60 column 250 x 4 mm 10 im particle diameter (VWR), with a mixture of (v v) dichloromethane (94 ) methanol (3 ) and glacial acetic acid (3 ) as mobile phase, at a flow rate of 1.0 mL min. The products are detected at 254 nm and matched to pure cortisol and prednisolone.

Cushings Disease Persisting After Pituitary Surgery

A significant proportion of patients with CD continue to have measurable cortisol levels after pituitary surgery, indicating total or partial failure in removing the adenoma. They may have invasive macroadenomas, and surgery was mandatory to reduce tumor bulk and correct visual failure from compression of the optic chiasm. After noncurative surgery, an immediate decision should be made as to whether a second surgical intervention is indicated. This may involve reexploration of the pituitary fossa or a full removal (total hypophysectomy) of remaining pituitary tissue. If a second procedure results in undetectable early morning cortisol concentrations, subsequent management is as outlined earlier. In those with evidence of continuing ACTH hypersecretion, further measures to control cortisol levels are necessary. In most cases, medical management with adrenolytic drugs is indicated, with metyrapone, ketoconazole, and mitotane being the most widely used. When initiating metyrapone, a test...

Hypogonadotropic Hypogonadism

Genetic defects in the development of the anterior pituitary cause hypopituitarism, including hypogonadotropic hypogonadism. During fetal development of the anterior pituitary gland, several sequential processes occur that affect cell differentiation and proliferation. Recent advances in molecular biology have revealed several steps that are required for pituitary cell line specification, and several genes have been identified to play a role in the control of these steps. Mutations in DAX1 gene cause X-linked adrenal hypoplasia congenita and mutations in the DAXl-related orphan nuclear receptor, steroidogenic factor-1 leptin and prohormone convertase-1 may influence GnRH release and processing of the GnRH receptor. The pituitary transcription factors, HESX-1, LHX3, and PROP-1, are important for gonadotroph development. Depending on the condition, different approaches for family counseling are needed. Despite recent advances, the pathophysiological basis of hypogonadotropic...

Granulosa and Theca Cells Both Participate in Steroidogenesis

Two steroidogenic pathways may be used for subsequent steroidogenesis (see Fig. 37.9). In theca cells, the delta 5 pathway is predominant in granulosa cells and the corpus luteum, the delta 4 pathway is predominant. Pregnenolone gets converted to either progesterone by 3 -hy-droxysteroid dehydrogenase in the delta 4 pathway or to 17a-hydroxypregnenolone by 17a-hydroxylase in the delta 5 pathway. In the delta 4 pathway, progesterone gets converted to 17a-hydroxyprogesterone (by 17a-hydroxy-lase), which is subsequently converted to androstenedione and testosterone by 17,20-lyase and 17 -hydroxysteroid dehydrogenase (17-ketosteroid reductase), respectively. In the delta 5 pathway, 17a-hydroxypregnenolone gets converted to dehydroepiandrosterone (by 17,20-lyase), which In the granulosa cell, under the influence of FSH, with cAMP as a second messenger, testosterone and androstene-dione are then converted to estradiol and estrone, respectively, by the enzyme aromatase, which aromatizes the...

Electron Microscopy

Electron Microscope Leptin Receptors

Hypocretin axons in synaptic contact with neuropeptide Y neurons containing leptin receptor in the monkey arcuate nucleus. A-D, Correlated light (A) and electron (B-D) micrographs demonstrating that in the monkey arcuate nucleus, two (arrows labeled 1 and 2 on A, B) black-colored hypocretin (HCRT) axon terminals are in close apposition to light stained neuropeptide Y (NPY)-containing neurons (curved arrows on A) HCRT axon 1 contacts a light NPY perikaryon that also expresses Golgi-associated black leptin receptor (LR) labeling (arrowheads on A-C). C and D are high-power magnifications of the boxed regions on B demonstrating that both HCRT boutons 1 and 2 establish asymmetric synaptic contacts (arrowheads on C, D) on the NPY- and leptin receptor-containing cell body (C) and on the NPY-containing dendrite (D). Note the abundance of mitochondria in the HCRT-containing axon terminal on D. Scale bars A, 10 xm B-D, 1 xm. (From 13) Figure 8. Hypocretin axons in synaptic contact...

Adrenocortical Hormones Corticosteroids

Examples of natural glucocorticoids include hydrocortisone (cortisol) and corticosterone (Figure 5.112), whilst aldosterone and desoxy-corticosterone (cortexone) (Figure 5.113) typify mineralocorticoids. Desoxycorticosterone has also been found in plants. Some common features of these molecules are the P-CO.CH2OH side-chain at C-17, and frequently an a-hydroxy also at this position. Ring A usually contains a A4-3-keto functionality. The 11 -hydroxy is essential for glucocorticoid activity. In aldosterone, the principal mineralocorticoid hormone, the methyl (cortisol) involves side-chain cleavage as seen in the biosynthesis of cardioactive glycosides (see page 243) and the same sequence of reactions is operative. From progesterone, the formation of desoxycor-ticosterone, corticosterone, and hydrocortisone (cortisol) (Figure 5.114) requires only a series of hydroxylation steps, catalysed by cytochrome hydrocortisone (cortisol) hydrocortisone (cortisol)

Clinical Features of Acute Retinal Necrosis

Development Vitreous Retina

Although numerous clinical findings have been described, none is pathog-nomonic for ARN. Keratic precipitates that usually appear as white, mutton fat deposits often occur during the onset of HSV or VZV ARN. In the chronic phase, white mutton fat-like precipitates may be replaced by pigmented precipitates (fig. 1). Although anterior granulomatous uveitis is ameliorated within 2 weeks, resolution of the prominent vitritis tends to be delayed compared to the anterior uveitis. The prominent vitreal inflammatory reaction and vitreous opacity usually resolve within 3 weeks, but a vitritis may recur 3-4 weeks later. Fibrotic changes of the vitreous decrease the mobility of vitreous gel, leading to the development of a posterior vitreous detachment which in turn produces vitreous traction on the peripheral retina, resulting in retinal detachment 20 .

The Hypothalamus And Addiction

Neuron 10x

The LH, in particular, has a history of being associated with drug addiction and drug abuse behavior. The relationship between the LH and both feeding and addiction may not be surprising since behavioral studies have shown cross-sensitization between 'natural' rewards and drugs of abuse. Both drugs of abuse and food restriction profoundly modulate LH-mediated ICSS and their effects can cross-sensitize.31,32 Moreover, leptin acts to reduce heroin self-administration33 and has can modulate LH-mediated ICSS. 14

The Hypothalamus Regulates Eating Behavior

Arcuate Nucleus Third Ventricle

A key player in the regulation of body weight is the hormone leptin, which is released by white fat cells (adipocytes). As fat stores increase, plasma leptin levels increase, conversely, as fat stores are depleted, leptin levels decrease. Cells in the arcuate nucleus of the hypothalamus appear to be the sensors for leptin levels. Physiological responses to low leptin levels (starvation) are initiated by the hypothalamus to increase food intake, decrease energy expenditure, decrease reproductive function, decrease body temperature, and increase parasympathetic activity. Physiological responses to high leptin levels (obesity) are initiated by the hypothalamus to decrease food intake, increase energy expenditure, and increase sympathetic activity. Hypothalamic pathways involving neuropeptide Y are important for the starvation response, while pathways involving the melanocyte-stimulating hormone are important for the obesity response.

The Adrenal Cortex Consists of Three Distinct Zones

The Three Zones The Adrenal Cortex

In the adult human, the adrenal cortex consists of three his-tologically distinct zones or layers (Fig. 34.1). The outer zone, which lies immediately under the capsule of the gland, is called the zona glomerulosa and consists of small clumps of cells that produce the mineralocorticoid aldosterone. The zona fasciculata is the middle and thickest layer of the cortex and consists of cords of cells oriented radial to the center of the gland. The inner layer is comprised of interlaced strands of cells called the zona reticularis. The zona fasciculata and zona reticularis both produce the physiologically important glucocorticoids, cortisol and corticosterone. These layers of the cortex also produce the

Negative feedback loops control hormone secretion

As well as being controlled by hypothalamic releasing and release-inhibiting hormones, the endocrine cells of the anterior pituitary are also under negative feedback control by the hormones of the target glands they stimulate (Figure 42.8). For example, the hormone cortisol, produced by the adrenal gland in response to adrenocorticotropin secreted by the an

Cyclic AMP Acts as a Second Messenger for a Number of Regulatory Molecules

Epinephrine is only one of many hormones, growth factors, and other regulatory molecules that act by changing the intracellular cAMP and thus the activity of PKA (Table 12-4). For example, glucagon binds to its receptors in the plasma membrane of adipocytes, activating (via a Gs protein) adenylyl cyclase. PKA, stimulated by the resulting rise in cAMP , phosphorylates and activates two proteins critical to the conversion of stored fat to fatty acids (perilipin and hormone-sensitive tri-acylglycerol lipase see Fig. 17-3), leading to the mobilization of fatty acids. Similarly, the peptide hormone ACTH (adrenocorticotropic hormone, also called corticotropin), produced by the anterior pituitary, binds to specific receptors in the adrenal cortex, activating adenylyl cyclase and raising the intracellular cAMP . PKA then phosphorylates and activates several of the enzymes required for the synthesis of cortisol and other steroid hormones. The catalytic subunit of PKA can also move into the...

Fivepoint Day Curve For Assessment Of Growth Hormone Status

Serum cortisol at time 0, followed by morning dose of hydrocortisone, sampling at 30 and 60 min. Breakfast is then taken, followed by sampling at 2, 3, and 5 h. Lunchtime hydrocortisone is taken, followed by sampling at 7 and 9 h. Evening hydrocortisone is then given, with further samples obtained at 9.5, 10, and 11 h. The aim is to have adequate circulating cortisol throughout the day, avoiding excessive peaks after each dose. Usually the basal sample indicates a value < 50 nmol L (1.8 g dL). Serum cortisol at 0, 1, 2, 3, and 4 h. The nadir value of serum cortisol after a single dose of metyrapone gives some indication of the regular therapeutic dose required.

A few dietary lipids may be toxic

The long-chain monoenoic acid, erucic acid (13c-22 1n-9 see Table 2.2) is present in high concentration (up to 45 of total fatty acids) in the seed oil of older varieties of rape (Brassica napus). When young rats were given diets containing more than 5 of dietary energy as high erucic rapeseed oil, their heart muscle became infiltrated with tri-acylglycerols. After about a week on the diet, the hearts contained three to four times as much lipid as normal hearts and although, with continued feeding, the size of the fat deposits (referred to as a lipidosis) decreased, other pathological changes were noticeable. These included the formation of fibrous tissue in the heart muscle. The biochemistry of the heart muscle was also affected. Mitochon-drial oxidation of substrates, such as glutamate, was reduced and the rate of ATP biosynthesis was impaired. The degradation of triacylglycerols that contain erucic acid is somewhat slower than with fatty acids of normal chain length and this may...

Preoperative Assessment Pituitary Adenoma Surgery

Corticotropin-releasing hormone (CRH), Cushing's syndrome, basal levels, 59 stimulation test, 58-60 Cortisol, perioperative monitoring, 176-178 primary cortisol resistance, 63, 64 replacement, see Hydrocortisone Craniopharyngioma, sampling, 62, 63 computed tomography, 61 corticotropin-releasing hormone, basal levels, 59 stimulation test, 58-60 cortisol assay, 57, 63 dexamethasone suppression test, 5558, 60 metyrapone testing, 61 periodic Cushing's syndrome, 63 pregnant patients, 63 primary Cortisol resistance, 63, 64 epidemiology, 51 etiology, 53 pathogenesis, 52 treatment, tumor removal, 189 prevalence, 1, 189 Pituitary tumor transforming gene (PTTG), pituitary adenoma pathogenesis, 11, 12 Postoperative management, acromegaly, 182-184 airway management, 124 complications, see also specific operations, cerebrospinal fluid rhinorrhea, 179 nasal airway, 178 vision, 178, 179 craniopharyngioma, 189, 190 Cushing's disease, 184-187 discharge, 179 fluid balance, 174, 175 gonadotropin tumors,...

Hypocretin Actions In The Adrenal Gland

Mineralocorticoid Actions The Brain

Using dispersed cell preparations of human adrenal tissues, Mazzochi and colleagues reported that orexin A but not orexin B stimulated basal cortisol secretion and enhanced the secretory response to angiotensin II, endothelin and ACTH.42 No significant effects were observed on aldosterone or catecholamine release from adrenal slices. As was the case in their studies on rat tissues, both hypocretin receptors were detected in human adrenal gland extracts, in this case the mRNA for the hcrtrl was most abundant. Similarly, as in rat tissues, the effect of orexin A appeared to be via activation of adenylyl cyclase. These same investigators also demonstrated the expression of the hcrtr2, but not the hcrtrl, gene in human pheochromocytomas and the ability of orexin A and orexin B to stimulate catecholamine release from these cells. The hcrtr2-mediated effect of the orexins was mediated not by adenylyl cyclase, but instead via activation of PLC and PKC.42 Opposing results were reported in an...

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