Treating Adrenal Fatigue

Adrenal Fatigue Recovery Workbook

This valuable book gives you all of the tools that you need in order to identify, manage, and treat the symptoms of adrenal fatigue syndrome. AFS is a medical problem that most doctors don't really know how to diagnose. The symptoms are often seen as being too vague to mean anything to medical professionals, and therefore people who suffer from this debilitating condition often suffer alone, and without medication. And those that DO get medicated often get put on something useless for this condition such as antidepressants or sleeping pills, which just add issues on to what you are already experiencing. If you are feeling down, tired, or depressed for no reason, there is a good chance that you are suffering from Adrenal Fatigue Syndrome There is no need for you to bear that alone! Why would you want to do that when you have a valuable resource in your hands? This book has everything you need to get help!

Adrenal Fatigue Recovery Workbook Summary


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Adrenal glands

There are two adrenal glands, one located on top of each kidney. These glands are composed of two distinct functional regions Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. Adrenal cortex. The adrenal cortex forms the outer portion of the adrenal gland and accounts for 80 to 90 of the weight of the gland. It is the site of synthesis of many types of steroid hormones such as Adrenal androgens. The predominant androgens produced by the adrenal cortex are...

Role of the Autonomic Nervous System in Pain

The effects of sympathetic nervous system activity are relatively brief in duration because of the rapid release and degradation of norepinephrine and acetylcholine released in the mediation of the fight-or-flight response. More sustained reactions to stressors or threat are mediated by neuroendocrine effects, a product of adrenal medulla activation. Sympathetic nervous system activation of the adrenal gland results in release of norepinephrine and epi-nephrine, mimicking sympathetic activity.

Estrogens And Their Involvement In Carcinogenesis

Estrogens are a family of related steroidal molecules that stimulate the development and maintenance of female characteristics and sexual reproduction, including regulation of the menstrual cycle, and have several other physiological functions. The most prevalent forms of human estrogens are estradiol and estrone, which are produced and secreted by the ovaries, although estrone is also synthesized in the adrenal glands and other organs.

Glucocorticoids and inhibitors of their biosynthesis as antitumor agents

Mitotane (o,p'-DDD) is an analog of the insecticide DDT that has been approved for use in the treatment of human inoperable cancer of the adrenal gland (adrenocortical cancer), and is also being used for treatment of canine Cushing's disease because of its cortex-selective adrenalytic activity. It completely obliterates adrenal production of glucocorticoids, mineralocorticoids, and adrenal gland-produced sex hormones.

Natural Products of Non Botanical Origin

Vertebrate tissue extracts have also been used as medicines for thousands of years. In fact, many prescriptions containing animal products are listed in Egyptian papyrus. In recent years, the pharmacology of various extracts, particularly of endocrine organs, has been investigated. Extracts from pituitary, thyroid and adrenal glands have been shown to exhibit dramatic effects when administered to vertebrates, and the active principles of these extracts have been isolated. The chemistry and biological activity of many important endogenous constituents of endocrine organs, such as epinephrine, thyroxine, corticosterone, insulin, prostaglandins, leukotrienes, endorphins, atrial natriuretic factor, nitric oxide, and endothelin have been elucidated, and information obtained from these studies has been used as a basis for the development of many clinically useful drugs.

The Role of Glucocorticoids in Physiology

Glucocorticoids are synthesized in the adrenal gland and participate in the regulation of physiological processes in a variety of organ systems (Miller and Blake Tyrrel, 1995). The majority of effects are mediated by the GR, although the MR is also able to bind glucocorticoids (Funder, 1992). In contrast to the MR, the affinity of the GR is much lower, such that receptor occupancy varies within the range of physiological glucocorticoid levels and thus ensures flexible responses to altered hormone concentrations in the blood. the lung glucocorticoids are able to promote maturation during development, and in the adrenal gland they are involved in the biosynthesis of catechola-mines. Furthermore, glucocorticoids participate in the supression of inflammatory reactions, which is achieved by repressing mRNA expression of cytokines and regulation of lymphocyte migration (Barnes and Adcock, 1993). Additionally, glucocorticoids are able to induce apoptosis of thymocytes (Chapman et al., 1996),...

Glutamate Receptors in Peripheral Tissues

A recent surge of publications (and this book) supports the presence, importance, and functionality of GluRs outside the CNS with unique distributions within various tissues and species. These tissues include adrenal medulla (Yoneda and Ogita, 1986 Watanabe et al., 1994 Hinoi et al., 2002a), peripheral nerves both myelinated and unmyelinated (Aas et al., 1989 Coggeshall and Carlton, 1998), bone (Chenu et al., 1997 Bhanga et al., 2001 Itzstein et al., 2001 Chenu, 2002 Gu et al., 2002 Hinoi et al., 2002), bone marrow (Genever et al., 1999), bronchial smooth muscle, endocrine pancreas (Betrand et al., 1992,1993 Gonoi et al., 1994 Inagaki et al., 1995 Molnar et al., 1995 Weaver et al., 1996 Liu et al., 1997 Gill et al., 2000 Morley, chapter 8, this volume), gut (Moroni et al., 1986 Shannon and Sawyer,1989 Burns etal., 1994 Tsai etal., 1994,1999), esophagus (Burns etal., 1994), duodenum, ileum, and descending colon (Burns et al., 1994), hepatocytes (Sureda et al., 1997 Storto et al., 2000...

Glucocorticoid Receptor Deficient Mice GRhypo Confirm a Major Role for the GR in Physiology

FIGURE 1 The regulatory system of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoids released after stimuli such as stress lead to physiological responses in a variety of organs. The HPA axis is a complex regulatory circuit that controls this release of glucocorticoids from the adrenal gland. Homeostasis is achieved by feedback inhibition of several of the involved factors in the hypothalamus and the anterior pituitary. These include corticotropin-releasing factor (CRF), arginine vasopressin (AVP), proopiomelanocortin (POMC), adrenocor-ticotrope hormone (ACTH), and prolactin (PRL). Signals from the hippocampus and the amygdala as well as from the immune system exert further influences on the control of the HPA axis. FIGURE 1 The regulatory system of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoids released after stimuli such as stress lead to physiological responses in a variety of organs. The HPA axis is a complex regulatory circuit that controls this...

Catecholamines As Neurotransmitters

While dopamine 3.4 and noradrenalin 3.2 are localized in their action, adrenalin 3.3 is also a circulatory hormone produced by the adrenal glands. The hormones are metabolized by the monoamine oxidase pathway, which converts the compounds via their imines to the aldehydes and which are then oxidized to the acids e.g. 3.32. There are two forms of monoamine oxidase. Monoamine oxidase A metabolizes nor-adrenalin and serotonin while dopamine is metabolized by monoamine oxidase B. Another metabolic pathway involves the COMT system, which converts the phenolic hydroxyl group that is meta to the side chain, to a methoxyl, e.g. 3.33. The methyl ether may then be metabolized via the monoamine oxidase pathway to a hydroxy-acid. The compounds may also be excreted as their sulfates. These metabolic changes prevent the neurotransmitter from binding to its receptor. A regulatory mechanism involves the re-uptake of noradrenalin. This leads to the inhibition of its release and thus it provides a...

Abnormal Thyroid Activity

The hormones of the thyroid, in concert with those of the adrenal gland and growth hormone from the pituitary, regulate energy utilisation, metabolic rate and growth. Since thyroid hormones are incorporated into the developing egg from maternal sources, they may also be involved in larval development, although their role in this is still far from clear. The main thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tetra- and triiodinated derivatives of 4-hydroxydiphenyl ether and as such have close structural similarities to other planar halogenated aromatic compounds such as PCBs, dioxins and DDT. It is therefore not surprising that such chemicals are those most suspected of inducing thyroid dysfunction by competing for receptors. As in mammals, thyroid function can be disrupted by action of pollutants at several sites, including production of thyrotrophin releasing hormone (TRH) from the hypothalamus, release of thyroid stimulating hormone (TSH) from the pituitary,...

Clinical Presentation

Most patients with SCC of the esophagus present with dysphagia, indicating occlusion of 50 to 75 of the lumen. They can also present with weight loss, odynophagia, and persistent chest pain unrelated to swallowing. Patients with EAC also present with recent onset dysphagia and weight loss. The appearance of EAC (Figure 11.2) is indistinguishable from SCC of the esophagus on endoscopy. EACs are predominantly located in the distal esophagus and tend to invade the gastric cardia and fundus. Tumors can appear polypoid, ulcerated, and even varicoid.1 The tumor can spread by direct extension to adjacent structures and via the lymph nodes to the neck, mediastinum, and upper abdomen. The tumor can also spread hematogenously to the liver, adrenal gland, and other organs. Radiographically, early cancer can appear as small sessile polyps, plaquelike lesions, or mucosal irregularities without a discrete mass. Advanced tumors may reveal infiltrating, ulcerative, or varicoid lesions on barium...

The HPA Axis Represents a Physiological System Involving Different Modes of GR Action

As this is explained by the elevated ACTH serum levels, it was interesting to analyze this parameter in GRdim dim mice, as well. In accordance with not significantly altered ACTH levels, we found no severe abnormalites in the morphology of the adrenal gland. However, mRNA expression of side chain cleavage enzyme (SCC) in the cortex and serum corticosterone levels were increased.

Pharmacology of the Ras Evidence for Angiotensin Receptor Subtypes and their Functional Roles

Endothelial cells in vitro have suggested that AT2 stimulation is antiproliferative (51) and that in pathological situations, stimulation of the AT2 receptor may limit excessive growth. In the adult, AT2 receptors are located predominantly in the brain, uterus, kidney, and adrenals. Various reports have claimed a role for the renal AT2 receptor in the adult animal in controlling vascular resistance (52) and the pressure-natriuresis relationship (53).

Immuneinduced Longlasting Changes In The Hpa System

Let us consider the changes in the biological substrate that may underlie such long-lasting cross-sensitization. Because largely different brain circuits are involved in the activation of the HPA system by immune and emotional stressors (Sawchenko, Brown, Chan, Ericsson, Li, Roland, & Kovacs, 1996), it was obvious to search for functional alterations within the HPA system rather than in stressor-responsive neural projections to the PVN. So far, long lasting alterations have been found at the level of the hypothalamic CRH neurons, of the pituitary gland and in feedback mechanisms. Before going into details of these changes it should be noted that single immune activation induces little or no long-term alterations in the resting levels of ACTH and corticosterone in the blood or the content of these hormones in the pituitary gland and adrenal gland respectively. Therefore, immune induced sensitization of the HPA system appears to be associated with altered responsivity rather than...

Immune Activation Induced Hpa Changes And Depression

Long-lasting immune stimulus induced and depression associated changes in the HPA system. Note the similarities of alterations at hypothalamic and pituitary levels, but not at the level of the adrenal gland (for details see text) Table 2. Long-lasting immune stimulus induced and depression associated changes in the HPA system. Note the similarities of alterations at hypothalamic and pituitary levels, but not at the level of the adrenal gland (for details see text)

The Neuro EndocrineImmune System

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

Hypothalamic PituitaryAdrenal Axis Normal Physiology

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

The Biosynthesis Of The Steroids

The biosynthesis of the hormonal steroids is regulated by a steroid cycle (see 5.65) in which a number of peptide hormones play a role. The biosynthesis is initiated by the hypothalamus in the brain. This is the source of peptide releasing hormones that stimulate the pituitary gland into producing the peptide trophic hormones, for example, ad-renocorticotrophic hormone (ACTH), and follicle stimulating hormone (FSH). The trophic hormones have the steroid synthesizing organs, such as the adrenal glands and the ovaries, as their target. The steroid hormones that are formed are then transported to their site of action where they produce a response. Although the major portion of the

Contributing To Oxidative Stress In Ad

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

Project Title Metabolism Of Digitalis Like Factors

Cortex are endogenous inhibitors of ouabain-sensitive sodium-potassium ATPase and by this mechanism affect blood pressure in mammals. The aim of this project is to define the chemical structure of DLIF and its biotransformation in tissue. Several chemical-identification techniques will be used to determine the structure of DLIF and its metabolic congeners. Biotransformation will be studied using in vitro metabolic techniques. Four independent measures of digitalis-like activity (immunoreactivity Na,K-ATPase receptor binding Na,K-ATPase catalytic activity and ion-transport activity) will be used to characterize the interaction of DLIF and its metabolic precursors and products with the sodium pump. This research will provide the much needed chemical structure of DLIF, define its structural changes during metabolism, and test the hypothesis that DLIF from adrenals are endogenous inhibitors of sodium-potassium ATPase. These factors may prove useful in elucidating the mechanism responsible...

Stress And The Immune System

Because stress activates both the hypothalamic-pituitary-adrenal-axis (HPA axis) and the sympathetic nervous system (SNS), it is not surprising to find that most acute stressors can modify the immune response. It is well known that plasma catecholamines released from the adrenals in response to stress, in addition to the adrenal glucocorticoids, can cause immuno-suppression. There are numerous experimental studies showing that various types of externally applied acute stressors (for example, electric shocks, social defeat, maternal separation, immersion in cold water) suppress some aspects of immune function. Similarly chronic stressors such as overcrowding, have been shown to suppress aspects of cellular and humoral immunity. Indeed, it is difficult to consider any aspect of cellular and humoral immunity that is not altered by some stressor (Maier, Watkins, and Fleshner, 1994).

Biosynthesis And Secretion

Progesterone is secreted by the corpus luteum during the second half of the menstrual cycle under the stimulus of LH (Figure 57-3). After fertilization, the trophoblast secretes hCG into the maternal circulation, which also acts through the LH receptor to sustain the corpus luteum. During the second or third month of pregnancy, the developing placenta begins to secrete estrogen and progesterone in collaboration with the fetal adrenal glands, and thereafter the corpus luteum is not essential. Estrogen and progesterone then continue to be secreted in large amounts by the placenta throughout gestation.

Manufacturing Of Cell Therapy Products

A variety of human- and animal-derived tissues, which can also include whole organs, serve as sources of cells for cell therapy products. Examples include skin, muscle, cartilage, bone, neural tissue, bone marrow, blood vessels, parenchymal cells from organs such as the liver, pancreas, and adrenal glands, and stem cells from adult and fetal tissues. A few general principles in the sourcing of these tissues are as follows (1) systems must be developed so as to allow the material to be traced back to the donor (2) steps must be taken to prevent the transmission of an infectious disease from the donor to the recipient and (3) adherence to aseptic procedures during procurement and initial processing are necessary to ensure the safety of the final product because terminal sterilization of cells is not possible.

Other Hormone Axes and Possible Levels of Disruption

Among the nuclear receptor superfamily there are receptors with unidentified ligands (hormones) called orphan receptors 108 . Some of these orphan receptors are now receiving names as their ligands are discovered. For example, the steroid-xenobiotic receptor (SXR) is a nuclear receptor that has been shown to activate transcription when bound by certain native steroid hormones or xenobiotics. SXR appears to induce transcription of xenobiotic and steroid hormone detoxification and metabolizing enzymes 37 . Steroidogenic factor-1 (SF-1) is still an orphan receptor because its ligand remains unidentified. However, it has been associated with regulation of some P450 steroidogenic enzymes, and more recently was shown to play an important role in the development of the gonad and adrenal glands in mice 109 and gonadal sex-differentiation in the chicken 110 . The obvious influence of former and present orphan receptors on development and reproduction in lab animals strongly

Steroidogenic Factor

Steroidogenic factor 1 (SF-1) was initially characterized as adrenal-gland specific factor that bound to conserved regulatory elements in the proximal promoter regions of steroid hydroxylases CYP11A, CYP11B2, and CYP21 (Parker and Schimmer, 1997). These regulatory elements contained a conserved AGGTCA consensus motif, suggesting that SF-1 was a member of the nuclear receptor superfamily. SF-1 was cloned from an adrenal gland library based on its homology to the RXRfi DNA-binding domain (Lala et al., 1992). SF-1 and the nuclear receptor ELP (embryonic long terminal repeat binding protein) are produced from a common gene through alternative promoter and splice site utilization (Tsukiyama et al., 1992 Ikeda et al., 1993). In total, a single SF-1 transcript and three alternatively spliced ELP transcripts have been identified (Ninomiya et al., 1995). In addition, SF-1 shares significant homology with the orphan receptor LRH-1 (also called PRH-1 and FRF) (Becker-Andre et al., 1993 Galarneau...

PGlycoprotein Pgp ABCB1

P-gp expression has also been demonstrated in kidney, adrenal gland, liver, colon, and lungs (Fojo et al., 1987 Gatmaitan and Arias, 1993). Additionally, P-gp expression in endothelial cells is lining the blood-tissue barrier that includes the brain capillaries (Thiebaut et al., 1989), implicating a protective functional role for P-gp through the active efflux of xenobiotics from the endothelial cytoplasm into the capillary lumen, as confirmed by Joly et al. (1995). P-gp is also expressed in the apical membrane of the placental syncytial trophoblasts, which faces the maternal blood compartment (Sugawara et al., 1988), and thus forms a functional barrier between the maternal and fetal blood circulations. Some peripheral blood mononuclear cells, such as cytotoxic T lymphocytes and natural killer cells, also express P-gp, suggesting involvement in cell-mediated cytotoxicity. Moreover, P-gp is expressed and functions in human hematopoietic stem cells, indicating it may contribute to the...

Depressionassociated Alterations In The Hpa System

Together with enhanced Cortisol responses to ACTH, these findings indicate that adrenal glands of depressed patients are hyper-responsive to circulating ACTH. In support of this, computer tomography studies revealed adrenal enlargement in major depressed patients (Nemeroff, Krishnan, Reed, Leder, Beam, & Dunnick, 1992) which disappears after successful treatment (Rubin, Phillips, Sadow, & McCracken, 1995). What exactly controls the changes in adrenal volume and responsiveness is not known but non-ACTH mechanisms including intra-adrenal CRH production (Van Oers, Hinson, Binnekade, & Tilders, 1992) and increased sympathetic drive (Dijkstra, Binnekade, & Tilders, 1996) are potential candidates.

Somatostatin Analogs Labeled with Gallium Radionuclides

68Ga-labeled DOTATOC was evaluated as a potential imaging agent for car-cinoid tumors by Hofmann et al. 40 . Dynamic PET scans were acquired over 180 min after intravenous injection of 80-250 MBq in eight patients with car-cinoid tumors. The group predefined 40 lesions by CT and or magnetic resonance imaging, and of these lesions, the PET imaging of 68Ga-DOTATOC identified 100 , whereas SPECT imaging of 111In-DPTA-OC identified only 85 . The PET imaging of 68Ga-DOTATOC also identified additional lesions not previously defined. Blood clearance was rapid and renal accumulation was low enough to allow delineation of adrenal glands 40 .

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

Given the complexity of findings, even within the broad category of patients with unipolar depression and the spectrum of marketed antidepressants with highly variable efficacy, it is not surprising that researchers look for unifying hypotheses. Unfortunately, those that have been proposed and tested such as definable norepi-nephrine or serotonergic types of depression have not been supported and those, such as the primacy of HPA axis dysfunction, have not been testable in the absence

Molecular Identity And Functional Features Of Vitamin C Transporters

And SVCT2 is obligatorily dependent on the presence of Na+, and the transport process exhibits a Na+ ascorbate stoichiometry of 2 1. This stoichiometry renders the transport process electrogenic, resulting in the transfer of a net positive charge into the cell per transport cycle. Therefore, the energy source for the transport process comes not only from the inwardly directed Na+ gradient, but also from the inside-negative membrane potential. The Michaelis constant for ascorbate is in the range 10-100 M for both transporters these values are within the physiologic concentrations of ascorbate in plasma. Though functionally very similar, SVCT1 and SVCT2 differ in tissue distribution pattern. The expression of SVCT1 is primarily restricted to epithelial cells in transport organs such as the small intestine, kidney, and liver. In contrast, SVCT2 is much more widely expressed, its expression being evident in the brain, placenta, ocular tissues (ciliary body, cornea, lacrimal gland, and...

O Sites Of Drug Biotransformation

Although other tissues, such as kidney, lungs, adrenal glands, placenta, brain, and skin, have some drug-metabolizing capability, the biotransformations that they carry out are often more substrate selective and more limited to particular types of reaction (e.g., oxidation, glu-curonidation).22 In many instances, the full metabolic capabilities of these tissues have not been explored fully.

Effects of Organ Size Blood Flow and Partition Coefficient on Distribution

Partition Coefficient Drugs

The various regions of the body are listed in decreasing order relative to blood flow per unit volume of tissue (adrenals highest and bone cortex lowest). This value essentially describes how fast a drug can be delivered to a body region per unit volume of tissue and reflects the relative rates at which tissues may be expected to come to equilibrium with the blood. How much drug can be stored or distributed into a tissue will depend on the size of the tissue (volume) and the ability of the drug to concentrate in the tissue (i.e., the partition coefficient between the organ and blood, KO B). For example, the blood flow per unit volume of thyroid gland (Table 1) is one of the highest in the body, whereas the gland itself is quite small. Thus, if partition of the drug between the thyroid and blood were approximately 1, we would expect to see that the drug in the tissue would rapidly come into equilibrium with that in the blood but that a relatively small total amount of drug would...

The Macrophage Theory Of Depression

Other major proinflammatory cytokines, IL-6, and TNF alpha. In addition to the direct effect of IL-1 on the HPA axis, there is controversial experimental evidence that macrophages may also secrete ACTH which could directly stimulate the adrenals to synthesize Cortisol. Thus an activated macrophage system in depression could both directly and indirectly contribute to hypercortisolaemia.

Free Radicals Derived From Catecholamines

Neuromelanin Anatomy

Catecholamines are themselves potent antioxidants but they are easily oxidized to highly neurotoxic o-quinones (Fig. 2). Vulpian (95) noted in 1856 that adrenal gland tissue exposed to air turns red. This red pigment was later identified as adrenochrome, but it was thought for many years that this pathway of catechola-mine metabolism never occurred in vivo. Recently, however, conclusive evidence has been obtained that this pathway does indeed occur in the body, particularly in the brain where it may be of great functional importance (91).

Treatment Considerations

Accompanying the idea that impairment in GR number and or function as a consequence of genetic or environmental factors (e.g. immune processes) contributes to the pathophysiology of major depression, recent studies have suggested that a possible mechanism by which antidepressants treat depression is through effects on the GR. A number of animal studies have shown that in vivo treatment with a range of antidepressant agents including both tricyclic antidepressants and selective serotonin reuptake inhibitors is capable of enhancing glucocorticoid feedback inhibition and increasing GR protein and or mRNA in key brain regions including the hippocampus (which has been shown to mediate an inhibitory influence on CRH in the paraventricular nucleus) (Holsboer & Barden, 1996). Antidepressants have also been found to facilitate glucocorticoid-mediated feedback inhibition and increase GR in animal models of HPA axis dysregulation including a transgenic model of impaired glucocorticoid...

The Contribution of Tyrosinase Activity to Stores of Catecholamines

Initially, we were perplexed to find that a week after the pigmented TH-null pups were born, they did make catecholamines and quantities were not insignificant during the first weeks of life. Levels of norepinephrine were especially high in heart and skin where quantities found in two week-old TH-nulls averaged 17 percent of wild-type littermates in heart and 23 percent of wild-type in skin. In the adrenal gland norepinephrine and epinephrine levels of the pigmented nulls amounted to less than 5 percent of wild-type littermates but considering the great quantity of these substances in the postnatal adrenal --that is a lot. And in the brain, there was measurable norepinephrine and dopamine in the pigmented TH-null, less than 10 percent of wild type values (5). These catecholamines were in normal locations glyoxylic acid-induced histofluorescence showed catecholamines present in sympathetically innervated structures all over the body and even in the dopamine-containing pathways of the...

Eicosanoid Catabolism

ENDOCRINE SYSTEM A number of endocrine tissues respond to PGs. In a number of species, the systemic administration of PGE2 increases circulating concentrations of adrenocorti-cotropic hormone (ACTH), growth hormone, prolactin, and gonadotropins. Other effects include stimulation of steroid production by the adrenals, stimulation of insulin release, and thyrotropin-like effects on the thyroid. The critical role of PGF2a in parturition relies on its ability to induce an oxytocin-dependent decline in progesterone levels. PGE2 works as part of a positive-feedback loop to induce oocyte maturation required for fertilization during and after ovulation.

Basic Pharmacology Of Vasopressin

VASOPRESSIN RECEPTORS The cellular effects of vasopressin are mediated mainly by its interactions with the 3 types of receptors, Vla Vlb, and V2. The Vla receptor is the most widespread subtype of vasopressin receptor it is found in vascular smooth muscle, the adrenal gland, myometrium, the bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting-duct, spleen, testis, and many CNS structures. V1b receptors have a more Limited distribution and are found in the anterior pituitary, several brain regions, the pancreas, and the adrenal medulla. V2 receptors are located predominantly in principal cells of the renal collecting-duct system but also are present on epithelial cells in the thick ascending limb and on vascular endothelial cells. Vasopressin receptors are GPCRs.

Role of cytochrome p450 proteins in the bioactivation of chemical carcinogens

The CYP1 family consists of two subfamilies, 1A and 1B the former comprises two proteins, 1A1 and 1A2, whereas only a single protein belonging to the latter, 1B1, has thus far been identified. CYP1A2 is almost exclusively a hepatic protein and appears not to be expressed at the protein level in most extrahepatic tissues, whereas CYP1A1 is largely expressed in extrahepatic tissues and is readily inducible in the liver.26 The CYP1B1 isoform is distributed in many tissues, and high constitutive expression was noted in the adrenals. CYP1 is probably the most conserved family within the phylogenetic tree so that the human proteins share extensive structural similarity and display similar substrate specificity to the orthologous rodent proteins, alluding to an important role for this family in a vital biological function.27

Steroid Hormonal Factors in Populations with Different Risk for Prostate Cancer

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

Glucocorticoid Resistance In Depression

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

Peroxiredoxin Based System in Cells and Organs of the Body

Although all six Prdx isoforms are present in the lung, Prdx 6 is predominant. High concentrations of Prdx 6 can be found in Clara cells in airways, and in type II epithelial cells and macrophages in alveoli 9 . In a study by Knoops et al. 186 , highest mRNA levels of Prdx 6 were detected in human thyroid gland, trachea, kidney, lung, adrenal gland, heart and colon. Prdx 3 and Prdx 6 appear highly expressed in healthy ovarian tissue as opposed to ovarian cancer, where several isoforms are dysregulated 187 . Prdx 4 is highly expressed in testis, ovary, heart, liver, skeletal muscle and pancreas, and a relatively high expression has also been described in spleen, thymus, prostrate, small intestine, colon, lung and placenta, whereas leukocytes and brain show low expression levels 68 . Prdx 2, besides being abundant in erythrocytes, is also highly expressed in the adrenal gland, brain and lung of rats, and relatively high expression was detected in rat spleen, gastric smooth muscle,...

The Failure to Thrive Phenotype

We found pathology in most organs of the TH-null pups that were examined. Another example of damaged tissue, one that has been published, is the adrenal gland 20 . Chromaffin cell structure is altered in the TH-null as was seen at the ultrastructural level. Chromaffin cell vesicles are depleted and an increase in rough endoplasmic reticulum is present in the TH-nulls. The few remaining chromaffin vesicles in the mutant pup line up proximally to the cell membranes. The expression of mRNA for proenkephalin and neuropeptide were increased.


Why is there such tight control of vitamin C concentrations, particularly in plasma There are two general explanations, i.e., either tight control is necessary to avoid harm or it is beneficial directly or indirectly. For the first possibility, tight control of plasma concentrations may be to avoid harm arising perhaps via potential prooxidant toxicity. Theoretically, ascorbic acid could act as a prooxidant under certain conditions especially at higher concentrations. For the second possibility, tight control of extracellular concentrations may allow higher local concentrations to occur under certain conditions, for example, by release of ascorbate from cells into tissue. These concentrations might act in a paracrine or autocrine fashion, perhaps participating in signal transduction. Such local ascorbate release has been described in cell systems and animals with respect to the adrenal gland (31,32) and brain (33). If there were strong advantages to tight control for these or other...

Co transmitters

Blaschko and colleagues found large amounts of ATP in the adrenal gland in the 1950s 79 . Release of ATP, proteins and adrenaline was demonstrated a decade later 80 . Although many laboratories reported multiple transmitters in invertebrate neurons 81 , purines were the first well-established vertebrate co-transmitters. Geoffrey Burnstock suggested that some neurons released more than one transmitter in a pioneering 1976 essay


Glucocorticosteroids are the synthetic derivatives of the adrenal gland hormone cortisol. At pharmacological doses they prevent or suppress inflammation and other immunologically mediated processes. These drugs are therefore used for a variety of inflammatory diseases such as allergic diseases, rheumatic disorders, renal diseases, bronchial asthma, skin and gastrointestinal diseases 122 . The anti-inflammatory and immunosuppressive activities of glu-cocorticosteroids are most likely due to the inhibition of the production of a wide range of cytokines, chemokines, eicosanoids, and metalloproteinases in many cell types. In macrophages they block the release of numerous cytokines (IL-1, IL-6, TNFa), inhibit the expression of the MHC class II antigens, depress production and release of pro-inflammatory PGs and LTs, and depress tumouricidal and microbicidal activities of activated macrophages 131 . In the case of neutrophils they inhibit neutrophil adhesion to endothelial cells, thereby...

Early Life Stress

Hippocampal volumes did not differ with respect to prior postnatal stress versus no-stress conditions in squirrel monkeys (Lyons et al. 2001). Rhesus monkeys raised in social isolation do not show hippocampal atrophy despite striking changes in other brain systems and associated behavior (Sanchez et al. 1998). In keeping with studies of humans (Sullivan et al. 2001 van Erp et al. 2004), however, significant heritabilities were discerned by paternal half-sibling analysis of squirrel monkey hippocampal volumes (Lyons et al. 2001). These and related findings suggest that the morphology of specific brain regions is determined in part by genes (Lyons 2002). Moreover, we found that small hippocampal volumes predicted increased stress levels of ACTH after pretreatment with saline or hydrocortisone (Lyons et al. 2007). Small hippocampal volumes may be a risk factor for, and not just an effect of, impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Similar...

Angiotensin Peptides

Many tissues (e.g., brain, pituitary, blood vessels, heart, kidney, and adrenal gland) express mRNAs for renin, angiotensinogen, and or ACE, and can produce renin, angiotensinogen, ACE, and AngI, II, and III. These local renin-angiotensin systems may influence vascular, cardiac, and renal function and structure.


Pheochromocytoma is a tumor of neuroectodermal origin that arises from the chromaffin cells (pheochromocytes) of the sympathoadrenal system. The term pheochromocytoma is derived from the chemical and pathological characteristics of a cell 'pheochromocyte' means a cell that takes on a 'dusky' color when exposed to chromium salts (Greek phaios and chroma mean dusky and color, respectively), and 'cytoma' means tumor. Almost 90 of these tumors are found in one or both adrenal glands, but they may be located anywhere along the sympathetic chain and, rarely, in aberrant sites. The 'rule of 10' has been used to describe pheochromocytoma 10 are extraadrenal and, of those, 10 are extra-abdominal 10 are malignant 10 are found in patients who do not have hypertension and, finally, 10 are hereditary.1 Those functioning tumors arising outside the adrenal medulla are termed extraadrenal pheochromocytomas, whereas those non-secreting extra-adrenal tumors are called paragangliomas.2 catecholamines...


In pregnancy, the growing fetus represents a semi-allogeneic graft which is protected against expulsion by suppression of local defense reactions. As the time of parturition approaches, this delicate balance is altered towards the selective use of inflammatory reactions providing effective mechanisms for delivering the baby. At the hormonal level this shift is characterized by the retreat of effectors which maintain uterine quiescence (progesterone, prostacyclin, nitric oxide and relaxin) 148 and the growing influence of labor-promoting agents such as estrogens, glucocorticoids, oxytocin, prostaglandins, corticotropin-releasing hormone (CRH), endothelins, PAF and cytokines (Fig. 8-9) 148-151 , The precise mechanisms by which the orchestra of hormones and local mediators is coordinated to act on the main target sites, the cervix and the myometrium, are not yet known. In a very complex and poorly understood manner, hormones and other signal molecules of fetal and maternal origin...

ACE inhibitors

AT-, receptor (mediates arlonal contraction, aldosterone & calecholScrtirte r& lGiSQ from Adrenal gland, OniriCtiflrt OF glOrtt& fUlai mes& ngium. 11 water rcaDsorpl on at renal 1.ubLily, thirst) AT-, receptor (mediates arlonal contraction, aldosterone & calecholScrtirte r& lGiSQ from Adrenal gland, OniriCtiflrt OF glOrtt& fUlai mes& ngium. 11 water rcaDsorpl on at renal 1.ubLily, thirst)


In depressed patients, basal plasma ACTH and cortisol have been found to be elevated (Holsboer 2000). Also urinary free cortisol, saliva free cortisol, or cerebrospinal fluid (CSF) cortisol levels are increased. Escape from dexa-methasone suppression was observed in a subgroup of depressed patients suggesting resistance to corticosteroid action. Hypercortisolism in depression is further supported by the enlarged adrenal glands of the patients. This indicates enhanced adrenal sensitivity to ACTH stimulation. The combined dexamethasone suppres-sion-CRF stimulation test (Dex-CRF test) appears to be the most sensitive tool to detect depression related changes in HPA axis reactivity. Moreover, several studies reported that normalization of the HPA axis precedes or parallels the clinical response to antidepressant treatment (Binder et al. 2009).


The estrogens are synthesized by the action of the enzyme aromatase on androstenedione or testosterone (Fig. 25.5). They are normally produced in relatively large quantities in the ovaries and the placenta, in lower amounts in the adrenal glands, and in trace quantities in the testes. In post-menopausal women, most estrogens are synthesized in adipose tissue and other nonovarian sites. About 50 to 350 g d of estradiol are produced by the ovaries (especially the corpus luteum) during the menstrual cycle. During the first months of pregnancy, the corpus luteum produces larger amounts of estradiol and other estrogens the placenta produces most of the circulating hormone in late pregnancy. During pregnancy, the estrogen blood levels are up to 1,000 times higher than during the menstrual cycle.


Other smaller scale experimental studies have shown that the bile salt export pump in human hepatocytes is regulated by FXR and not LXR, as it was inducible by 22(R)-hydroxycholesterol and appeared to have different ligand binding determinants in the receptor than chenodeoxycholic acid (191). FXR has also been suggested to regulate the organic solute transporters a and P in human adrenal gland, kidney, and intestine (192). Although the exact physiological function of these transporters has not been defined, there may be a role in bile acid resorption.

Class A GPCRs

Expression of a melanocortin receptor accessory protein, which is only expressed in cells derived from the adrenal gland 186, 187 - In most studies, ligand binding and localization experiments were not done, preventing conclusions from being drawn on whether the mutant MC2Rs are defective in cell surface expression, ligand binding, and or signaling.

Steroid Deactivation

The liver contains cytochrome P-450 dependent mono-oxygenases, and reducing and conjugating enzymes that convert hormones into water soluble products which can be more easily excreted. Mono-oxygenase enzymes of the liver, which are closely related to enzymes in the adrenal gland and the gonads, are affected by copper, mercury and organotin, PCBs, PAHs, pulp mill effluent and municipal wastewater, but are unaffected by most organochlorine pesticides.2 Such changes

The Trpm Subfamily

Ing channels that reduce the inward driving force for Ca2+. TRPM4 proteins are detected in the following heart, pancreas, intestine, lung, thymus, uterus, vomeronasal organ, brain, fat tissue, adrenal gland, kidney, spleen, cultured aortic endothelial cells, and bone marrow-derived mast cells (Vennekens and Nilius, 2007). TRPM5, which is expressed in taste receptor cells, is a downstream depolarizing signal transducer of G protein-coupled receptors in taste buds. TRPM5 appears to be important, though not indispensible, for the transduction of sweet, amino acid, and bitter stimuli (Perez et al., 2002 Zhang et al., 2003 Damak et al., 2006).


Corticotropin-releasing factor (CRF) is best known as a hormone that is secreted by the hypothalamus and that stimulates adrenocorticotropic hormone (ACTH) release from the pituitary, which results in the production of cortisol by the adrenal glands. Specifically, CRF is localized to neurons of the paraventricular nucleus in the hypothalamus, which send axons to the median eminence. CRF-containing cells are also localized to other hypothalamic nuclei, such as the medial preoptic area and the dorsomedial, arcuate, and mammillary nuclei (DeSouza and Grigoriadis 2002), as well as to the amygdala and bed nucleus of the stria terminalis (Keller et al. 2006). Besides the median eminence, CRF axons are present in the cerebral cortex, brain stem (including the locus coeruleus), and spinal cord. To date, two CRF receptors have been identified, CRF1 and CRF2. CRF1 receptors are expressed in the pituitary, cerebral cortex, hippocampus, amygdala, and medial septum, and CRF2 receptors are...