The Natural Thyroid Diet

Thyroid Factor

Thyroid Factor is a program that was created by Dawn Sylvester to help women deal with thyroid issues. Dawn Sylvester is a 57 years old lady that has worked with 1,000's of real women. She has over the time tried to investigate the underlying reason why majority of women lose energy and also struggle with belly fat and fatigue as they age. It is a comprehensive program thatcomprises of Thyro pause, 11 kinds of thyroid saving foods that will work to help you boost fat burning Free T3. The program also teaches you all the hidden causes of thyroid which are making you fat and later a highly reliable Thyroid reboot plan which is an excellent plan you need to tackle your weight. Additionally, there are tips to reduce bulging fat fast and eventually obtain a healthy body. You also get several bonuses all aimed at helping you solve all the problems that comes with being overweight. The three bonuses you get are 21 Day Thyroid weight loss system, 101 Thyroid boosting foods and Thyroid Jumpstart Guide. Read more...

Thyroid Factor Summary


4.8 stars out of 19 votes

Contents: Ebooks
Official Website:
Price: $37.00

Access Now

My Thyroid Factor Review

Highly Recommended

The author has done a thorough research even about the obscure and minor details related to the subject area. And also facts weren’t just dumped, but presented in an interesting manner.

When compared to other e-books and paper publications I have read, I consider this to be the bible for this topic. Get this and you will never regret the decision.

The Control of Thyroid Hormones The Paradigm for Endocrine Control

The earliest indication of a functional link between pituitary and thyroid is probably attributable to Niepce (1851) who noted pituitary enlargement in goitrous cretins. Evidence of pituitary influence over thyroid function first derived from the work of Allen (1916) and Smith (1916) in tadpoles. Smith and Smith (1922) were later able to restore metamorphosis in hypophysectomied tadpoles by the injection of homogenized bovine pituitary, providing an elegant demonstration of the thyrotropic properties of the pituitary. Further support came from Loeb and Basset (1928) and Aron (1929) who independently demonstrated by histological means that bovine pituitary extract stimulated the thyroid. Although Aron et al. (1931) observed a reciprocal relationship between TSH and thyroid hormone (TH), it was Kuschinsky (1933) who concluded that TSH was regulated by TH, and Salter (1940) who supplied the term pituitary-thyroid axis. The intensive research into automatic weapon control systems during...

The Relationship between TSH and Thyroid Function

The loss of thyroid gain resulting from thyroid damage reduces overall loop gain. The quality of loop control diminishes and a new equilibrium is established which tolerates a higher error. The pituitary gland, which is undamaged, responds with an increase in TSH. It was established earlier that the performance of the loop in controlling T4 was dependent wholly on loop gain. The rise in TSH is a reflection of the fall in loop gain and in no sense compensates for it. Figure 5 indicates that the relationship between T4 and TSH with falling thyroid efficiency is far from linear. By the nature of log-linear based control loop responses, the fall in T4 is minimal, even at a 50 reduction in thyroid efficiency, while the TSH has risen well outside its normal range. This is because, in log-linear systems, the smallest changes in input are associated with the (proportionately) largest changes in output. A further point of clinical importance emerges here. It is clear that two factors (omitting...

The Relationship between TSH and Thyroid Function at Different Levels of TRH

Figure 6 expresses the relationship between TSH and T4 calculated for 10 different levels of TRH demand designed to cover the range of T4 in a healthy population in steps of 10 nm L from 70 to 140 nmol L. At each setting of TRH, the TSH level was calculated for thyroid efficiencies (g2) varying from 100 (health) to 20 (severe damage). The result is a family of constant TRH curves each defining the relationship between TSH and thyroid efficiency at a different TRH setting. These curves are linear and parallel, as was observed empirically in the rats subjected to progressive hypothalamic damage (Reichlin et al., 1972) on a log-linear plot. Their gradient is equal to pituitary gain.

The Interaction between Pituitary and Thyroid in Producing Control

The performance of the pituitary and thyroid can be analyzed independently by breaking or opening the loop and graphing the dose-response curves of each Figure 7. The plot in Figure 6 has been superimposed with a family of constant thyroid gain curves. The intersections between the lines of constant TRH and curves of constant thyroid gain represent the equilibrium between TSH and T4 for a given thyroid gain at any particular level of TRH demand. Figure 7. The plot in Figure 6 has been superimposed with a family of constant thyroid gain curves. The intersections between the lines of constant TRH and curves of constant thyroid gain represent the equilibrium between TSH and T4 for a given thyroid gain at any particular level of TRH demand. component at different settings. Thus, pituitary performance is demonstrated by varying the error (i.e. lowering the T4 level stepwise against a constant TRH input) and measuring TSH, and thyroid performance by varying TSH and measuring the resulting...

Effects on the Thyroid Axis

Medical illness is often associated with a state of functional thyroid deficiency known as euthyroid sick syndrome (ESS) (Papanicolaou 2000). In its early stages, ESS is characterized by normal thyroid-stimulating hormone (TSH) and thyroxine (T4) levels, but by reduced levels of triiodothyronine (T3), which is the more biologically active form of thyroid hormone. In later stages of ESS, T4 levels are also decreased. Evidence suggests that proinflammatory cytokines promote this condition via direct effects on the thyroid gland, as well as by inhibition of enzymes responsible for peripheral conversion of T4 to T3, especially in the liver (Papanicolaou 2000). It is well known that decreased thyroid functioning is associated with the development of symptoms of depression, and functional abnormalities of the thyroid axis are observed in many patients with major depression who do not have clinically obvious thyroid disease (Musselman and Nemeroff 1996).

Potential Effects of Endocrine Disrupting Chemicals on Thyroid Function

The thyroid gland is present in all vertebrates. Its activity is principally controlled by the thyroid stimulating hormone (TSH) released by the pituitary. The hormones produced by the thyroid gland are iodinated tyrosine compounds, and are found in the body in two forms thyroxine (T4) and, at lower levels, the more active form in mammals, triiodothyronine (T3). In addition to their role in modulating the general metabolic activity of an organism, these hormones, operating via permissive action, have been found to influence embryo differentiation and development, the functioning of the reproductive and immune systems, the development of olfactory senses, social behaviour and intelligence.36 Disruption of thyroid functions in vertebrates has been suggested to constitute a potential threat to many vital functions. For example, there is a possibility that disruption to the thyroid hormone levels during embryogenesis could result in disturbed behaviour patterns in the adult form, possibly...

Thyroid Disease and Thyroid Stimulating Hormone Receptor Mutations

Similar to the rhodopsin receptor disorders, activating and inactivating mutations of the thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) underlie many cases of thyroid disease. The TSHR mutations disrupt TSH signaling by blunting the Gs-mediated stimulation of adenylyl cyclase. Disruption of TSHR may result in dysregulation of the TSH function and result in the abnormal growth of thyroid hormone-secreting cells. Hyperthyroidism, for example, can result from activating germline mutations that are located in the TSHR TM domains. By contrast, thyroid adenomas and multin-odal goiter (25-31) result from a variety of somatic mutations in other regions of the TSHR. For example, a rare constitutively active TSHR mutation in the first TM domain results from a Gly substitution at the conserved 431Ser position (28). Mutations with similar outcomes have been identified in nonautoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia) (25,26,28,32,33). These variants are...

Thyroid Functions and Drugs Affecting Them

The thyroid gland, a 20 g tissue structure on the upper segment of the trachea, controls essential physiological function by its ability to make, store, and secrete two thyroid hormones. These functions include regulation of growth and general development, primarily by controlling DNA transcription and therefore protein synthesis. This in turn results in various enzymatic activities. Deficiencies in thyroid hormones have catastrophic effects in early life, the extremes of which can be manifested in cretinism by dwarfism and severe mental retardation. Another action is referred to as the calorigenic effect. This is evidenced by the increase in basal metabolic rates in organs such as the kidneys, heart, and liver, as well as in skeletal muscles. Valid mechanisms by which these effects can be satisfactorily explained have been elusive. Thermal regulation should be included in this area, as shown by the fact that thyroid secretions can be stimulated by a decrease in temperature....

Thyroid And Antithyroid Drugs

The thyroid gland is the source of two fundamentally different types of hormones, iodothyronines and calcitonin. The iodothyronine hormones thyroxine (T4) and triiodothyronine (T3) are essential for normal growth and development and play an important role in energy metabolism. Calcitonin is discussed in Chapter 61. The principal hormones of the thyroid gland are iodine-containing amino acid derivatives of thyronine T4 and T3 (see Figure 56-1). T4 is a prohormone that is converted to the biologically active form, T3. The 3'-monosubstituted compounds are more active than the 3',5'-disubstituted molecules. The affinity of iodothyronines for thyroid hormone receptors (TRs) generally parallels their biological potency. biosynthesis of thyroid hormones The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a complex glycoprotein that forms the bulk of thyroid follicular colloid. The thyroid gland uniquely stores great quantities of potential hormone in this...

Project Title Thyroidal Regulation Of Cardiac Sodiumpotassium Atpase Expression And Energetics

Summary Na+, K+-activated adenosine triphosphatase (Na, K-ATPase) is a ubiquitous energy transducing integral plasma membrane protein whose activity is of critical importance to the normal function of virtually all animal cells. In the heart the enzyme represents the cellular receptor for digitalis glycosides and its abundance and activity is significantly stimulated by the action of thyroid hormone (T3). The stimulatory effect of T3 on energy metabolism of the heart in vivo is a consequence of the direct actions of the hormone on cardiac myocytes as well as the increase in cardiac contractile work (cardiac output. in response to enhanced energy demand by other tissues. It has also been noted that the heart in hyperthyroid humans and animals manifests a reduction in functional reserve and maximal work capacity that is associated with a marked reduction in myocardial creatine-phosphocreatine pool. Such hearts are hence prone to fail if stimulated to work at or near maximal levels. The...

Biological Activities of Chemokines and their Receptors in Thyroid Cancer

Epithelial thyroid tumors include well-differentiated papillary and follicular (PTC and FTC), poorly differentiated (PDC), and anaplastic carcinomas (ATC). We showed that transformation of thyroid cells with oncogenes typical of PTCs activates a transcriptional program that includes the expression of chemokines, and of their receptors. Chemokines were described originally to regulate the chemiotaxis of leukocytes into inflammatory sites. Furthermore, chemokines can be secreted by tumor cells and recruit, into the tumor site, inflammatory cells. To exploit the eventual role of these molecules in thyroid cancer, we screened human thyroid cancer-derived cells and human thyroid tumor samples for the expression of the chemokine receptors CXCR2 and CXCR4, and their ligands, CXCL1, IL-8, and SDF-1. We found that both well differentiated (PTC) and undifferentiated (ATC) thyroid cancers expressed the chemokine receptors CXCR2 and CXCR4. Most of the PTC and some ATC-derived cell lines also...

Antithyroid Drugs And Other Thyroid Inhibitors

A large number of compounds interfere either directly or indirectly with the synthesis, release, or action of thyroid hormones (Table 56-2). Inhibitors are classified into four categories (1) antithyroid drugs, which interfere directly with the synthesis of thyroid hormones (2) ionic inhibitors, which block the iodide transport mechanism (3) high concentrations of iodine itself, which decrease release of thyroid hormones and may also decrease hormone synthesis and (4) radioactive iodine, which damages the gland with ionizing radiation. Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis, including inhibitors of the peripheral deiodination of T4 to T3, 3 adrenergic receptor antagonists, and Ca2+ channel blockers. MECHANISM OF ACTION Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin...

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,...

Thyroid gland

The thyroid gland is a butterfly-shaped structure lying over the ventral surface of the trachea just below the larynx. This gland produces two classes of hormones synthesized by two distinct cell types Thyroid hormones (T3 and T4) synthesized by follicular cells Thyroid hormones. Internally, the thyroid consists of follicles, which are spherical structures with walls formed by a single layer of epithelial cells called follicular cells. The center of each follicle contains a homogenous gel referred to as colloid. Thyroid hormones are stored here as a component of the larger molecule, thyroglobulin. The amount of thyroid hormones stored within the colloid is enough to supply the body for 2 to 3 months. Derived from the amino acid tyrosine, thyroid hormones are unique because they contain iodine. At this time, its incorporation into thyroid hormones is the only known use for iodine in the body. There are two thyroid hormones, named for the number of iodides added to the tyrosine residues...

Thyroid Hormone

A series of studies of thyroid augmentation of antidepressant response have been reported by Prange and associates (320). In their first study, 20 euthyroid patients (16 women and 4 men) most of whom were diagnosed as unipolar retarded depression, were given imipramine (150 mg) plus 25 mg of triiodothyronine (T3). Reductions in HAM-D scores were greater and occurred more rapidly in the T3 group. Other studies from the same research group found that women with nonretarded depressions also responded to T3 augmentation but men did not. In a study of T3 augmentation of amitriptyline, patients who were treated with 40 mg of T3 with amitriptyline (100 mg) improved more rapidly than those on 20 mg of T3 or placebo women had better responses than men (321). An open trial using clomipramine had similar results (322). Several other studies have also found that patients who were unresponsive to tricyclic antidepressants improved with the addition of T3 in doses of 25-50 mg (323-326). SSRI...

O Antithyroid Drugs

Hyperthyroidism (excessive production of thyroid hormones) usually requires surgery, but before surgery the patient must be prepared by preliminary abolition of the hyperthyroidism through the use of antithyroid drugs. Thiourea and related compounds show an antithyroid activity, but they are too This drug is useful in the treatment of hyperthyroidism. There is a delay in appearance of its effects because propyl-thiouracil does not interfere with the activity of thyroid hormones already formed and stored in the thyroid gland. This lag period may vary from several days to weeks, depending on the condition of the patient. The need for three equally spaced doses during a 24-hour period is often stressed, but evidence now indicates that a single daily dose is as effective as multiple daily doses in the treatment of most hyper-thyroid patients.81

The Concept of Control

Endocrine systems are control systems, but descriptions of their function and operation often confuse the question of what controls, what is being controlled, and what the term control implies. There has been a tendency to dissect out the components of a system for study, with consequent failure to take account of their behavior within the intact loop. The medical literature speaks of the control of thyroid function (Purves, 1964), the control of thyrotrophin (Hershman and Pitman, 1971), regulation of TSH (Bogdonove, 1962), hypothalamic control of thyrotroph-thyroidal function (Shibusawa et al., 1956), etc. There is nevertheless a simple and universal definition of control which is central to the discussion which follows. 1. Control is the restraint placed upon a process in order that it perform in a predetermined manner. Thus, with respect to thyroid function, it is the thyroid hormone concentration in the plasma pool that is being controlled, not the thyroid gland. The restraint is...

The Implications of Hormone Replacement for Hormone Control

It will be appreciated that an endocrine gland may fail by degrees. As is clear from Figure 5, early loss of transfer factor (in this case the thyroid's) results in a curvilinear fall in output level as the trophin level rises exponentially. A point is reached, however, when the slope becomes linear, indicating that saturation has been reached and that the transfer factor or gain has fallen to zero. Zero gain for the thyroid means zero gain for the entire loop and, inevitably, total loss of output control. The administration of hormone replacement cannot reestablish control it can only provide a level of hormone determined by the dose given. Clinically, the implications of this state may be minor or critical. The serum levels of thyroxine do not vary from day to day or even week to week in health, so that the regular administration of a long half-life medication such as thyroxine is readily adjusted according to the TSH level. Serum Cortisol, on the other hand, fluctuates in a...

The Clinical Interpretation of Trophin Levels

A raised TSH level among clinically euthyroid individuals (Hedley et al., 1971 Evered et al., 1975) whose T4 level lies within the reference range has been widely reported after thyroid surgery, symptomless thyroiditis (Gordin et al., 1974) and after radioiodine treatment (Toft et al., 1973 Tunbridge et al., 1974) for hyperthyroidism (Figure 10). The term subclinical hypothyroidism was applied to this group of patients many years ago (Evered et al., 1973) and appears appropriate in as far as the raised TSH reflects suboptimal loop control for thyroid hormone levels.

The Endocrine Index

Reference was made earlier to the gain constant of the thyroid as the parameter which determines the output of the gland (T4) for any given input (log TSH). The gain constant defines the slope of the relationship between log TSH and T4, and will be expected to vary with the functioning mass of thyroid tissue. Although the TSH level is widely regarded as the best index of thyroid function, it reflects not the gain constant of the thyroid, but its gain factor which is influenced by variations in hypothalamic set point and pituitary function. The singular importance of the gain constant is that it defines the performance of the thyroid independently of these other variables it is a true parameter of thyroid function. The same applies to the ACTH cortisol, LH-FSH sex steroid, STH IGF, insulin glucose, PTH calcium, and other systems. TSH is normally the only stimulus to thyroid hormone release, and the majority of hormone produced by the thyroid is in the form of T4. The thyroid index...


The largest superfamily of eukaryotic transcription factors comprises nuclear receptors and contains more than 150 proteins, including steroid nonsteroid nuclear hormone receptors and orphan receptors (Mangelsdorf et al., 1995 Perlmann and Evans, 1997). The nuclear hormone receptors are ligand-inducible transcripton factors that have critical roles in the control of development, differentiation, homeostasis, and reproduction. These diverse actions are initiated by their specific binding to small lipophilic molecules such as steroid and thyroid hormones, retinoids, and vitamin D3 (Harvey and Williams, 2002 Haussler et al., 1997 Ruberte, 1994). The majority of nuclear receptors are orphan receptors for which no ligand was initially identified (Giguere, 1999). During recent years, the identification of novel ligands for a number of these receptors, which include the retinoid X receptor (RXR) (Mangelsdorf et al., 1992), peroxisome proliferator-activated receptor (PPAR) (Devchand et al.,...

Making Sense of PPIs in Wnt Signaling

Scaffoldfor beta-catenin degradation in Wnt signaling pathway (modified after KEGG PATHWAY Wnt signaling pathway (2008)). Details of Wnt signaling are explained in the text. B. Twenty PPIs reportedfor ANP32A. A.The proteins shown in beta-catenin scaffold are CSNK1E casein kinase 1, epsilon DVL1 dishevelled, dsh homolog 1 (Drosophila) SENP2 SUMO1 sentrin SMT3 specific peptidase 2 FRAT1 frequently rearranged in advanced T-cell lymphomas GSK3B glycogen synthase kinase 3 beta PPP2CA protein phosphatase 2 (formerly 2A), catalytic subunit, alpha APC2 adenomatosis polyposis coli 2 CSNK1A1L casein kinase 1, alpha 1-like isoform AXIN1 axin 1 ANP32A Acidic leucine-rich nuclear phosphoprotein 32 family member A CTNNB1 catenin (cadherin-associated protein), beta 1. +p indicates increased phosphorylation. B. Symbols in grey-shaded boxes indicate PPIs detected by Stelzl et al. (2005). Nineteen ANP32A interacting proteins that were retrievedfrom PPI databases are APEX1 APEX nuclease...

Modification of Receptor Binding Elements

For therapeutic purposes it is usually necessary to modify the signaling via just one subtype of GPCR out of many expressed by the same cell type. For example, naturally occurring constitutively active receptor mutants were implicated in Jansen-type metaphyseal chondrodysplasia (Schipani et al. 1995), autosomal dominant non-autoimmune hyperthyroidism and toxic thyroid nodules (Paschke 1996 Khoo et al. 1999), certain forms of cancer (Allen et al. 1991 Parnot et al. 2002), and familial nephrogenic diabetes insipidus (Barak et al. 2001). Existing

Previous pagepage41next page

A number of neurotransmitter substances are used peripherally as hormones, including amines and peptides (see above). Although they are chemically identical, they represent a different pool of chemical messengers because they generally do not pass the blood-brain barrier. However, several hormones readily pass the blood-brain barrier and have direct effects in the central nervous system. The hypothalamus releases severeal different releasing factors that travel through portal vessels to the anterior pituitary. There they initiate the release of trophic hormones, which travel through blood vessels to the various endocrine glands and trigger release of their hormones. Hormones from the adrenal, gonadal, and thyroid glands feed back to the pituitary gland and the brain, regulating releasing factors and trophic hormones. Hormones act through membrane-bound metabotropic receptors, as well as to intracellular receptors that directly initiate gene expression. Soluble Gasses

Neuroendocrine Disorders In Major Depression And Irs Activation

IRS activation not only involves specific immune (mentioned under 2.1. and 2.3.) and metabolic alterations (mentioned under 2.2. and 3), but also neuroendocrine changes such as hyperactivity of the HPA axis, and alterations in HP-thyroid (HPT) axis function and in the peripheral and central turnover of 5-HT. Axis. A wide spectrum of alterations in HPT-axis function has been observed in patients with IRS activation or systemic non-thyroidal illnesses, caused by infection, sepsis, or injury (Kushner, 1982 Kaptein, 1986 Nicoloff & LoPresti, 1991). Abnormal low total T3 or T4, lowered basal TSH, and increased free T4 concentrations, may be observed in those conditions (Wartofsky & Burman, 1982 Wehmann, Gregerman, Burns, Saral, & Santos, 1985 Kaptein, 1986 Nicoloff & LoPresti, 1991 Hermus, Sweep, van der Meer, Ross, Smals, Benraad, & Kloppenborg, 1992). IL-ip and IL-6 are important mediators of the IRS-related alterations in HPT-axis function, e.g. IL-6 administration may suppress serum...

Nuclear Hormones Focus On Steroids

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

Nutrient Carriers Versus Diffusionmediated Uptake

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system 29 and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y+ system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na+-dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B0+ system), appear to be confined to the...

Developing a Novel Biopharmaceutical

Since the introduction of biotechnology to health sciences, many new, previously unavailable proteins and peptides for therapeutic purposes have been introduced. The agents include (1) factors that influence hematopoietic cells and blood coagulation, (2) interferons and cytokines for anti-infective and cancer therapy, (3) hormones and derivatives, (4) enzymes and derivatives, and (5) recombinant proteins for vaccines. Examples of hematopoietic growth and coagulation factors are ery-thropoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), clotting factors Vila, VIII, and IX, GPIIb IIIa inhibitors that affect platelet function, direct thrombin inhibitors, and antihemophilic factor. Several interferons are now available for the treatment of viral infections and some cancers. Numerous hormones, including glucagon, somatotropin, calcitonin, somatostatin, thyroid-stimulating hormone, thyrotropin-releasing hormone (Protirelin),...

The Major Facilitator Superfamily

The major facilitator superfamily (MFS) includes almost 4000 different transporter proteins. The MFS family members transport diverse substrates including sugars, polyols, drugs, neurotransmitters, Krebs cycle metabolites, phosphorylated glycolytic intermediates, amino acids, peptides, organic and inorganic anions and many more (http ) 60-63 . These transporters function by uniport, symport or antiport mechanisms, and may possess either 12 64 , 14 65 or 24 66 trans-membrane helices (TMHs), with a common evolutionary ancestor 67 . Examples of human MFS transporters are glucose uniporters (GLUTs), the vesicular monoamine transporter 1 and 2 (VMAT1 and VMAT2), the thyroid hormone transporter (MCT8) and the organic anion transporter (OAT) family.

Effects on Synthesis Storage Release Transport and Clearance of Hormones

There are many ways in which endocrine disrupters might affect the levels of hormones circulating in the bloodstream. For example, lipid soluble hormones, including sex steroids, thyroid hormones and glucocorticoids, are transported bound to carrier proteins and their effects are to some extent influenced by the levels of these proteins in the blood. In mammals, oestrogens increase the concentration of sex hormone binding globulin (SHBG) in the plasma, whereas androgens decrease it.81 It is possible, therefore, that EDs might have similar effects.

Specific Metabolic Features of Women with Bipolar Disorder

And a propensity towards higher waist circumferences 10 . Obese patients with either BD or schizophrenia are more likely to be women 30 , and weight gain has been shown to be associated with female sex 31 . An evaluation of data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) demonstrated greater rates of obesity in bipolar women (31 ), compared to bipolar men (21 ) in contrast, there were greater rates of overweight in bipolar men (38 ), compared to women (22 ) 32 , a finding consistent with previous studies 33 . Women with BD appear to have a higher likelihood of increased waist circumference than men with BD, suggesting a sex-specific vulnerability to IR in BD. Changes in weight and appetite are found more commonly in women than in men with BD 34, 35 . Higher rates of thyroid and eating disorders are seen in women with BD 36 . Factors that influence the onset and maintenance of obesity in BD include both gender and eating behavior 37 . Similarly,...

Hormonal Regulation of Calcium Metabolism

Calcium fluxes through the gut, skeleton and kidney, the three major organs involved in normal serum calcium regulation. Calcium homeostasis is normally in equilibrium (i.e. the same quantity of calcium that enters the body by dietary consumption is excreted via the kidney and the gut) (Figure 6.1). These fluxes are continually regulated by diverse hormonal stimuli, some directly related to calcium and phosphorus metabolism, such as parathyroid hormone (PTH), vitamin D and calcitonin, secretion of which is regulated by ionized seric calcium, therefore called calciotropic hormones (Figure 6.1). Other hormones, not regulated by calcium levels, hence not considered calciotropic, have also a considerable influence on calcium balance. These non-calciotropic hormones include sexual hormones, thyroid hormone, adrenal steroids and growth factors. Other factors that may influence calcium balance include medicaments and physical activity.1 Considering all these important physiological roles,...

Biological Properties Medicinal Applications Of Laminaria

As discussed under the chemical properties, a dietary supplement, Laminaria, is rich in several constituents that can be very beneficial to the health. Its high iodine content proves to be a great natural boon for the thyroid gland to prevent goiter. Apart from its high calcium, potassium, magnesium, iron, and trace minerals such as manganese, copper, selenium, and zinc, it provides vitamins B1 and B2 as well as chromium which is instrumental in blood sugar control and helps to keep diabetes in check. In Europe, Laminaria is basically harvested for a main source of alginate in the food industry, an emulsifying and binding agent used in the production of many foods like ice cream, toothpaste, cereals, and cosmetics as well as in paints and films (

Potential Mechanisms Of The Cns Effects Of Cytokines

There are a myriad of mechanisms by which cytokines can effect nervous system function. These include induction of secondary cytokines that affect neuronal function (Licinio, Kling, & Hauser, 1998), release of stress hormones that are known to cause mood and cognitive alterations (Meyers & Valentine, 1995), the development of autoimmune thyroid disease (Jones, Wadler, & Hupart, 1998), alterations of neurotransmitter function that are important in frontal-subcortical neuronal circuitry (Ho, Lu, Huo, Fan, Meyers, Tansey, Payne, & Levin, 1994), and possibly effects on cerebral endothelium (Meyers & Valentine, 1995). Additionally, most recent studies utilize recombinant cytokines. There is a recent report on the use of natural interferon in asymptomatic HIV-positive individuals that reported fewer side effects than is gener-

Dimers May Allow for Conformational Switches Underlying Receptor Cross Talk and Other Forms of Allosterism

At first glance, the model depicted in Fig. 4.2c does not seem to have any specific merit in providing a parsimonious explanation. With a little imagination, it is possible to draw ever- more complicated arrangements, in which arrays of receptors are confronted with tubes of G proteins of various stoichi-ometries. The arrangement in Fig. 4.2c specifically suffers from the drawback that it does not solve the foot size shoe size problem 20 - But, it does have the advantage that it can account for mutually antagonistic cross-talk in het-erodimeric receptors. Such a finding has been observed for the A2A adenosine receptor and the D2 dopamine receptor, which can assemble into a heterodi-mer 67, 68 . This dimer formation is thought to be of interest for the treatment of Parkinson's disease, because the mutual inhibition of the two receptors is predicted to have an impact on movement control by the corpus striatum activation of the A2A receptor impedes D2 receptor coupling and is thus...

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.

BLPI as a signaling molecule

LPI has a wide range of biological activities including, for example, increases in intracellular Ca2+ concentration in rat liver cells (Baran and Kelly, 1988) and opening of two pore-domain K+ channels, such as TREK-1 (Maingret et al., 2000). As a derivative of a long-chain fatty acid, some of its actions have been ascribed to its capacity to interact physically with membranes (its critical micellar concentration is around 75 mM), and this seems to be the case with respect to its actions, and those of other lysophospholipids, on K+ channels which can be correlated with the shape of the molecules (Patel et al., 2001). However, there are many systems where the effects of LPI are more easily explained by it interacting with a specific receptor, for example, in its mitogenic action in a differentiated thyroid cell line (Falasca et al., 1995). Although this action was not sensitive to PTX, it was inhibited by tyrphostins AG18 and AG561 and so is dependent on tyrosine kinase activity.

Intracellular Receptors for Drugs and Hormones

Receptors for certain hormones are located intracellularly and can regulate the synthesis of specific proteins within the cell 51,52 . Ligands are thought to gain access to these receptors by diffusing through the cell membrane. These receptors contain a single polypeptide chain of between 400- and 1000 amino acid residues. In addition, they contain a binding site for hormones at the C-terminal region and a binding site for DNA located in the middle of the molecule. When cells are homogenized and centrifuged, these receptors are found in the soluble fraction, suggesting that they are cytosolic. Binding to the receptor requires that the hormone be sufficiently lipophilic to pass through the cell membrane. Hormones bind to receptors at the C-terminal portion of the peptide which contains hydrophobic amino acid residues. Hormone-receptor interaction produces a conformational change in the molecule, which exposes the hydrophilic DNA binding domain, which is positively charged. The...

Time resolved fluorescence based assays in screening for biocatalytic activities

Time-resolved fluorometry is a well established technique in routine immunodiagnostic work, as employed in the DELFIA system (7, 10). Diagnostic kits are available for a wide range of analytes for major diagnostic areas such as thyroid function, fertility, oncology, and pre- and neonatal screening. For researchers requiring high sensitivity and wide dynamic range, the many advantages of the time-resolved fluorometric technology have been brought to areas such as protein labelling, use of DNA probes and cytotoxicity assays. The possibility to use four different labels gives this technology a unique potential to develop quadruple label screening assays.

Growth Metabolism and the Stress Response

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

Other Emerging Effects of CB1 Antagonists

It has been demonstrated that rimonabant attenuates the antitumor effects of anandamide-related compounds or other cannabinoid agonists in thyroid, breast, and prostate cancers (Bifulco et al., 2001 Grimaldi et al., 2006 Portella et al., 2003 Sarfaraz et al., 2005), the effects being dependent on CB1 receptor activation. In other tumor types, like glioma, rimonabant failed to revert the antiproliferative action of cannabinoid agonists whereas the selective CB2 antagonist, SR144528 (Sanchez et al., 2001) or a combination of the CB1 CB2 antagonists can partially prevent this effect (Jacobsson et al., 2001). However, a 48-h preincubation with these antagonists seems to enhance the AEA-mediated cell death of glioma cells, suggesting a more complex mechanism of action (Maccarrone et al., 2000). Considering the antitumor properties of the cannabinoid receptor agonists, it could be expected that cannabinoid receptor antagonists, like rimonabant, if used alone, would enhance proliferation of...

Growth Hormone And The Hypothalamicpituitarysomatotrophic Axis

It appears that cholinergically mediated suppression of somatostatin plays a significant role in regulating nocturnal GH release (Ghigo et al. 1990 Mendelson et al. 1978 Peters et al. 1986). Factors that can enhance GH release include estrogen (Devesa et al. 1991b Ho et al. 1987), thyroid-releasing hormone, vasoactive intestinal peptide, hypoglycemia, sleep, exercise, and stress (Devesa et al. 1992 Muller 1987 Uhde et al. 1992). Finally, GH exerts a negative feedback inhibition of its own secretion (Devesa et al. 1992 Muller 1987). It appears to act at the level of the hypothalamus and or median eminence to stimulate somatostatin release (Devesa et al. 1992). It may also inhibit GHRH release (Devesa et al. 1992). GH also stimulates the production of somatomedin-C insulin-like growth factor 1 (IGF-1) in peripheral tissues, including liver. Somatomedin-C in turn has a dual inhibitory feedback effect. It directly suppresses GH secretion at the pituitary level and stimulates somatostatin...

Biochemistry And Toxicity 151 Biological Persistence

TCDD may alter the levels of certain hormones through its influence on the enzymes that metabolize primarily xenobiotic compounds. For instance, TCDD induces one form of UDP-glucuronosyltransferase (UDPGT), a phase II enzyme that increases a chemical's solubility by adding glucuronic acid. In addition to xenobiotics, UDPGT also conjugates and enhances the excretion of thyroxine (T4), causing reduced serum levels of this thyroid hormone in rats. 101 Among the resultant complications is a perturbation of an important biological feedback system The pituitary responds to low T4 with increased secretion of thyroid-stimulating hormone (TSH). When prolonged, this may lead to thyroid tumors, 102 a sensitive endpoint in TCDD-exposed rats.103

Egg Numbers and Viability

While fertilisation and hatch rates have long formed the basis of many standard toxicity tests owing to the rapidity with which they can be carried out with small fish such as danios and minnows, they also provide valuable information on endocrine disruption. In many cases, abnormal development may be caused by the chemicals interfering with key developmental processes involving cellular signalling mechanisms, rather than by simple toxicity or chromosomal damage. Although the exact mechanism by which embryonic and larval development is controlled is not yet fully understood, it involves both the steroid and thyroid hormones and a range of intra- and intercellular messengers that are now covered by the broader definitions of endocrinology. As a result of the widespread use of early life stages for toxicity testing there is a vast literature on the types of developmental abnormalities which can occur, but so far very little on how much of this is really endocrine disruption and how much...

The Regulated Production of Superoxide by Nadph Oxidase Isoforms

The production of ROS by nonphagocytic NAD(P)H oxidase isoforms plays a role in the regulation of intracellular signaling cascades in various nonphagocytic cell types, including fibroblasts, endothelial cells, vascular smooth mucle cells, cardio-myocytes, sperm, and thyroid tissue 169,192 . Non-phagocytic cells appear to utilize structural homologues of gp91PHOX. Several such homologues have recently been identified. Muscle cells and fibroblasts are the main source of superoxide in the normal vessel wall.

Plausibility of Adverse Effects of EDCs Mechanisms of Gonadal and Accessory Reproductive Organ Differentiation

While a switch in the course of differentiation of the gonads does not occur in mammals due to environmental factors, it is possible for EDCs to influence the early processes of testicular differentiation. There is a direct relationship between the number of Sertoli cells and the number of germ cells the number of Sertoli cells is correlated with daily sperm production in rats 132 . This has led to the hypothesis that prenatal exposure to estrogen may permanently reduce Sertoli cell numbers, resulting in subsequent decreases in adult sperm output 27 . This could occur, for example, via an effect on FSH or thyroid hormones. It has been shown that, during testicular differentiation, FSH levels are posi tively related to Sertoli cell number and subsequent testicular sperm production 133,134 .In addition, an experimental decrease in circulating thyroid hormone during testicular differentiation results in an increase in adult testicular sperm production 135 . There are thus multiple...

New patient assessment

Investigations should be conducted with the aim of excluding other causes for sensory neuropathies including diabetes, deficiencies of B vitamins, syphilis, and thyroid dysfunction. The immunological status of the individual can be estimated using recent HIV viral load and CD4 counts. Nerve conduction studies may be performed as baseline evaluations, but do not necessarily exclude DSP or ATN if normal, because of their lack of sensitivity in assessing small fiber function. If available, quantitative sensory testing (QST) and epidermal innervation assessment provide useful diagnostic information in the assessment of HIV and other small fiber neuropathies (see Chapter 4, Sensory testing and clinical neurophysiology and Chapter 7, Diagnostic algorithms for painful and nonpainful peripheral neuropathy in the Practice and Procedures volume of this series).

Blocking Chemokines and or Chemokine Receptors as Approaches to Cancer Therapy

Higher expression levels of selected chemokine receptors have been reported in many cancer cells compared to their normal counterparts. A partial list includes, for breast (CXCR3, CXCR4, CCR7, CXCR7, CCR5),ovarian (CXCR4), prostate (CXCR4, CXCR5, CCR9, CCR5, CX3CR1), pancreas (CXCR4, CXCR1 2, CCR6), bladder (CXCR4), colon (CXCR3, CXCR4, CCR6, CCR7, CXCR1 2), stomach (CCR7), and thyroid (CXCR4) (Wu, Lee, Chevalier, & Hwang, 2009). It appears that three receptors, CCR7, CXCR4, and CXCR7, are prominently expressed in cancer and more specifically in metastasis (Meijer, Ogink, & Roos, 2008 Zlotnik, 2006). Preclinical data suggest that inhibition of CXCR4 by neutralizing antibodies, siRNA against CXCR4, and antagonists such as AMD3100, MSX-122, or CTCE-9908, inhibit growth and reduce metastasis (Kim et al., 2008 Liang et al., 2004 Slettenaar & Wilson, 2006 Yoon et al., 2007). Another peptide-based CXCR4 receptor antagonist, TN14003, inhibited primary tumor growth and metastasis of head and...

Project Title Ubiquinone And Mitochondrial Oxidative Disorders Of Agin

In addition, a decline of aerobic energy metabolism in the affected tissue is often associated with the progression of these neurodegenerative diseases. A decline in aerobic metabolism has been observed in aging tissues. Ubiquinone(coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form(ubiqionol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo and for which there exists enzymic mechanisms which can regenerate it from its oxidized product formed in the course of its antioxidant function. Tissue ubiqionone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism they increase...

FoLLide StimuLating Hormone SignaL Transduction And Molecular Targets

Follicle-stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (Walker and Cheng, 2005). FSH is secreted from the pituitary gland under the control of the gonadotropin-releasing hormone (GnRH) and it is essential for normal reproduction in both male and female mammals. In female, FSH induces the maturation of ovarian follicles by targeting a receptor expressed specifically on granulosa cells, and by stimulating estradiol and inhibin secretion. High estradiol levels, produced by mature follicles, lead to a positive feedback on the hypothalamus, which causes the LH surge responsible for ovulation. Secretion of inhibin causes an inhibition of FSH release from the pituitary. In male, FSH is responsible for the initiation of spermatogenesis at puberty, whereas in adult it may play a role, together with testosterone, in maintaining sperm production. FSH binds...

Class Iii Antiarrhythmics

Amiodarone has adverse effects involving many different organ systems. It also inhibits metabolism of drugs cleared by oxidative microsomal enzymes. It contains iodine in its molecular structure and, as a result, has an effect on thyroid hormones. Hypothyroidism occurs in up to 11 of patients receiving amiodarone.43 The principal effect is the inhibition of peripheral conversion of T4 to T3. Serum reverse T3 (rT3) is increased as a function of the dose as well as the length of amiodarone therapy. As a result, rT3 levels have been used as a guide for judging adequacy of amiodarone therapy and predicting toxicity.44

Molecular characterization

Despite the fact that adenosine receptors were well characterized and partially purified, the two first adenosine receptors cloned, A1 and A2a, came from a library of orphan receptors from the dog thyroid (Maenhaut etal. 1990 Libert etal. 1991). Soon the same receptors were cloned from rat and humans (Mahan etal. 1991 Furlong etal. 1992), and a related receptor, the A2b receptor, was cloned from rat brain (Stehle et al. 1992). Whereas these receptors had all been predicted from extensive pharmacological studies, the fourth receptor, A3 was more unexpected (Zhou et al. 1992). These four adenosine receptors have now been cloned from a variety of mammalian and non-mammalian species (Table 11.1). A1, A2a, and A2b receptors are well conserved among mammals, whereas A3 receptors show considerable structural variability.

G a Protein Subunit Disrupted in Disease

The Gsa subunit, encoded by the GNAS gene on 20q13, is one multiple-gene product that results from alternative promoters and exon splicing. Gsa is the ubiquitously expressed Ga subunit that is required for receptor-mediated cAMP production. A number of widely distributed activating variants, such as Arg201Leu, lead to McCune-Albright's syndrome (MAS) (81,82), in which patients can develop fibrous dysplasia (FD) of bone, cafe-au-lait skin lesions, gonadotropin-independent sexual precocity, or tumors (or nodular hyperplasia) of pituitary somatotrophs, thyroid, or adrenal cortex with associated hormonal oversecretion (83). Similar mutations have been identified in cases of adrenocorticotropin-independent macronodular adrenal hyperplasia (84) and premature breast development (85). The activating Gsa variants result in various phenotypes that are influenced by constitutive cAMP production (81). The GNAS1 gene imprinting causes patients who have inherited Gsa mutations from their fathers to...

Helicobacter Pylori And Malignant Lymphoma

Isaacson and Wright in 1983.42 This malignant lymphoma is classified into marginal-zone B-cell lymphoma with post-germinal center state in the revised WHO classification.43 This kind of lymphoma appears not only in the stomach, but in the thyroid gland, salivary gland, orbit, lung, and mammary gland. However, the stomach is the most prevalent site. This is usually a low-grade lymphoma and might have been diagnosed as pseudolymphoma or reactive lymphoid hyperplasia. However, their monoclonality was established by clonal analysis with Southern blot of polymerase chain reaction.

M Amiodarone Hydrochloride

Hospital or under specialist supervision) Cautions liver-function and thyroid-function tests required before treatment and then every 6 months (see notes above for tests of thyroid function) hypo-kalaemia (measure serum-potassium concentration before treatment) chest x-ray required before treatment heart failure elderly severe bradycardia and conduction disturbances in excessive dosage intravenous use may cause moderate and transient fall in blood pressure (circulatory collapse precipitated by rapid administration or overdosage) or severe hepa-tocellular toxicity (monitor transaminases closely) administration by central venous catheter recommended if repeated or continuous infusion required infusion via peripheral veins may cause pain and inflammation ECG monitoring and resuscitation facilities must be available during intravenous use acute porphyria (section 9.8.2) interactions Appendix 1 (amiodarone) Contra-indications (except in cardiac arrest) sinus bradycardia, sino-atrial heart...

Betaadrenoceptor blocking drugs

Thyrotoxicosis Beta-blockers are used in pre-opera-tive preparation for thyroidectomy. Administration of propranolol can reverse clinical symptoms of thyrotoxicosis within 4 days. Routine tests of increased thyroid function remain unaltered. The thyroid gland is rendered less vascular thus making surgery easier (section 6.2.2).

Activation of Endocannabinoid Biosynthesis

The HPA axis activity is homeostatically controlled by means of a negative feedback mechanism comprised of both rapid (nongenomic) and delayed (genomic) components, resulting in the reduction of CRH-induced secretion of ACTH from the pituitary gland (Dallman and Jones, 1973 Dayanithi and Antoni, 1989 Jingami et al., 1985 Keller-Wood and Dallman, 1984 Keller-Wood et al., 1988). There are conflicting reports on the genomic versus nongenomic mechanisms controlling fast feedback at the pituitary gland (Dayanithi and Antoni, 1989 Hinz and Hirschelmann, 2000). On the other hand, recent works done in acute hypothalamic slices demonstrated that GCs dose-dependently (Di et al., 2003) and within 1 min (Malcher-Lopes et al., 2006) suppressed excitatory neuronal inputs to all kinds of PVN neuroendocrine cells, including those that regulate the HPA axis, the hypothalamic-pituitary-thyroid (HPT) axis, and the circulating levels of oxytocin and vasopressin. The threshold concentration for this...

Tolerability and Safety

In general, mood-stabilizing medicines have to be reasonably well tolerated because patients are expected to take them week in and week out for many years - often indefinitely. There is a tendency for doctors to underestimate the adverse impact of medicines on their patients. The most important adverse subjective effects of psycho-tropic drugs that are used to treat bipolar disorder tend to be tiredness, sedation, and weight gain. In addition, lithium can produce tremor, increased urine volumes, and thyroid dysfunction. Attention to minimizing these problems (by optimizing doses) is essential for good adherence to prescribed medicines.

Uses of the PCR in research and clinical diagnosis

Exfoliative cytology specimens can be collected by washing, scraping or aspiration techniques. These specimens could include cells found in urine, sputum, pleural effusions or from uterine cervix. The analysis of such specimens by the PCR is being used clinically to obtain a rapid indication of the presence of neoplastic disease, e.g. following cervical smear testing (McPherson et al., 1991). In other instances, the PCR has been used in the identification of presurgical lymph node metastases in melanoma patients (Schwurzer-Voit et al., 1996) and to confirm diagnosis of acute promyelocytic leukaemia and chronic myelogenous leukaemia by detecting specific chromosomal translocations (Drexler et al., 1995 Wujcik, 1996). The technique has also been used to monitor response of these diseases to chemotherapeutic agents and to predict disease progression. Recently, researchers at the Columbia Presbyterian Medical Center in New York City have patented a new test for thyroid cancer (Lewis,...

Painful Mononeuropathies

Carpal tunnel syndrome (CTS) is one of the most commonly encountered neuropathies in clinical practice and is described as an uncomfortable condition of the wrist and hand that is precipitated by repeated flexion and extension of the wrist causing increased pressure on the median nerve. Although CTS is commonly considered a condition of repetitive movement that may be related to particular occupations, it is also associated with medical conditions including diabetes, rheumatologic and thyroid disorders. CTS symptoms include pain that may radiate up the forearm, numbness, tingling, and reduced sensation in the hand and wrist and the symptoms often worsen at night or after use of the hand. The symptoms usually begin in the dominant hand, although in more than half the cases, the disorder is bilateral.

The Neuro EndocrineImmune System

Among vertebrate species, the neuro-endocrine-immune system is responsible for many complex, inter-related physiological processes including neuronal, homeostatic, reproductive and immune functions. There are four main types of hormone polypeptides, eicosanoids, steroids and thyroid hormones. Reflecting the inter-dependency of the neuro-endocrine and immune systems, hormones, neuropeptides and other neurotransmitters are known to be produced by some immune cells and play a role in the regulation of the immune system, while endocrine and nervous tissues express receptors for many substances produced by the immune system.2 The major focus of interest in endocrine disruption has been reproduction and sexual differentiation and development, with most attention being given to effects associated with steroid hormones and, to a lesser extent, the thyroid hormones. The steroid hormones are metabolically derived from cholesterol, and are biologically stable, lipophilic chemicals which are...

Technetium Radiopharmaceuticals

mTcO can be used to image the thyroid, salivary glands and ectopic gastric mucosa. To target Tc to different sites it is necessary to prepare complexes of the isotope to affect its physicochemical properties. The first generation of Tc radiopharmaceuticals were based on relatively simple coordination complexes of Tc. The distribution of these compounds, which are referred to as Tc-essential compounds, depends upon the charge, size, stability and lipophilicity of the metal complexes. With the increasing demand for compounds that target specific receptor systems, there has been a shift toward tagging biomolecules with Tc as a more rational means of achieving site selectivity. This latter class of compounds are referred to as Tc-tagged radiopharmaceuticals.

Potential Effects of Endocrine Disrupting Chemicals on Reproductive Function

During early development, the mammalian embryo displays both male (the Wolffian ducts) and female (the Mullerian ducts) characteristics. Development is governed genotypically, although differentiation is modulated by the steroid and thyroid hormones. Female sexual differentiation appears to be the default pathway, with female characteristics developing unless dictated otherwise by genetically directed production of male hormones. The presence of a Y-chromosome is responsible for induction of the Leydig cells to produce testosterone, under which influence the embryo develops a male phenotype. During critical periods of fetal development, exposure to sex steroids can exert irreversible changes on sexual development and subsequent adult behaviour.9 Thus, the mammalian system is potentially at risk from endocrine disruption during early differentiation the period of sexual maturation is clearly also a particularly susceptible phase. In contrast, exposure to hormonally active...

Orphan Nuclear Receptors An Emerging Family of Metabolic Regulators

The nuclear receptor superfamily includes more than 70 members sharing a conserved domain structure and general mode of action. Prototype members of the family function as transcription factors whose activity is modulated by classical endocrine hormones such as gonadal and adrenal steroids, vitamin D, and thyroid hormone. It was soon appreciated that the nuclear receptor family contained many members whose activity was not regulated by classical hormones The search for ligands and functions associated with these putative receptors, referred to as orphan nuclear receptors, became an active and rewarding field of research. The discoveries that specific orphan nuclear receptors respond to nonclassical hormones such as vitamin A derivatives, prostanoids, sterols, and fatty acids, combined with the observation that nuclear receptor response elements are present in the promoter regions of genes encoding enzymes involved in cellular metabolism, suggest that orphan nuclear receptors may be...

Effects of Endocrine Disrupting Chemicals EDCs

The list of chemicals that are known to affect humans, domestic animals, and or wildlife via functional developmental toxicity or endocrine mechanisms includes TCDD, polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-furans (PCDFs), methylmercury, ethinyl estradiol (EE), alkylphenols, plant sterols, fungal estrogens, chlordecone, dibromochloropropane (DBCP), o,p'-DDD (Mitotane), o,p'-DDT, and p,p'-DDE. In addition to these xenobiotics, more than 30 different drugs taken during pregnancy have been found to alter human development as a consequence of endocrine disruption 35 . These drugs are not limited to estrogens like diethylstilbestrol (DES). EDCs are known to alter human development via several mechanisms besides the estrogen receptor (ER) this includes binding to the AR or retinoic acid (RAR, RXR) receptors, and by inhibition of steroidogenic enzymes or the synthesis of thyroid hormones 35 . Recent findings on the effects of background levels of PCBs on the...

Inhibitors Of The Rasrafmek Signalling Pathway And Farnesyl Transferase

The Ras proteins belong to a large family of GTP-binding proteins (GTPases), and were among the first proteins identified as cell growth regulators. In normal cells, the Ras activity is controlled by the GTP GDP ratio. About 25 of human tumors, including nearly all pancreatic cancers and at least 30 of colon, thyroid, and lung tumors, have undergone an activating mutation in one of the Ras genes that leads

GPCR Mutationinduced Disease

Another group of naturally occurring constitutively active receptors includes those in which point mutations have been shown to enhance the basal level of signaling and thereby cause human disease (see also Chapters 8 and 15). Well established examples occur in class A e.g., basal thyroid stimulating hormone receptor (TSHR) activity resulting in hyperthyroidism or adenomas , class B e.g., basal parathyroid hormone receptor subtype 1 (PTH1R) signaling resulting in chondrodysplasia , and class C receptors basal calcium-sensing receptor (CaSR) activity resulting in hypocalcemia . These, as well as other examples are summarized in Table 5.2. thyroid adenoma Abbreviations TSHR thyroid stimulating hormone receptor. LHR luteinizing hormone receptor. PTH1R parathyroid hormone receptor subtype 1. CaSR calcium-sensing receptor. FSHR follicle stimulating Abbreviations TSHR thyroid stimulating hormone receptor. LHR luteinizing hormone receptor. PTH1R parathyroid hormone receptor subtype 1. CaSR...

Brain Pituitary Axis

CBs are also involved in neuroendocrine regulation of hormone secretion since cannabinoid exposure affects reproduction, lactation, food intake, and stress. Exposure to D9-THC inhibits the release of gonadotro-phin (LH), prolactin, growth hormone, thyroid-stimulating hormone, and stimulates the release of the stress hormone corticotrophin (for review Murphy et al., 1998 Pagotto et al., 2006). Effects of eCBs on endocrine axis involve several actors. For example, GH inhibition is mediated through somatostatin activation while AEA suppresses prolactin release in male rat through the activation of the tuberoinfundibular dopaminergic system (Pagotto et al., 2006). Direct effect on thyroid gland has been reported (Porcella et al., 2002) the colocalization of CB1 and corticotrophin-releasing hormone (CRH) mRNA, reported in hypothalamic neurons of

Mucosal Brush Border Membrane Lipid Transporters

Other lipid-binding proteins have been identified, including GP330 (also called megalin), CD36, SR-BI, caveolin, and more recently, the FATP4 (131). GP330 is a member of the low-density lipoprotein receptor gene family and is an endocytic receptor expressed in many absorptive epithelia, including the kidney proximal tubules, Type II pneumocytes, mammary epithelium, and thyroid follicular cells (132). It has been demonstrated that GP330 is involved in the renal uptake of polybasic drugs (132-134), vitamin B12 (134), cholesterol carrying lipoproteins (135), albumin (136), and proteases (133). Whether GP330 is expressed in the intestine is still uncertain (132).

Radiation Treatment of Cancer Pain

Radiation therapy is used for pain relief if the tumor is invading bone or soft tissue. It is also used for decreasing the size of tumor mass. If bone metastases are limited to few sites, external beam radiation therapy may relieve pain and symptoms. In case of widely disseminated bone metastases, hemi-body irradiation has been utilized. This can produce complete pain relief in 20 of patients and partial pain relief in 75 of patients. Systemic radiopharmaceuticals have also been used in pain caused by various metastatic diseases. These agents are specific to each tumor. For example, one can provide pain relief in patients with well-differentiated thyroid cancer. Pain relief can occur within the first week of treatment and lasts for 2-4 months.

Somatostatin Analogs Labeled with Positron Emitting Halogen Radionuclides

Thyroid and abdominal background activity 6,55-57 . Radioiodinated carbo-hydrated N-terminal conjugates of SSTr analogs showed encouraging improvements in the biodistribution and tumor uptake kinetics 54 . With these improvements in developing iodinated SSTr analogs, it is anticipated that SSTr analogs labeled with 124I will be reported in the near future.

PCB 169 A Putative Antiandrogen

Hallmarks of antiandrogenic action, at a dosage level that produces significant reproductive toxicity suggests that the Ah receptor agonists may be affecting these tissues via alternative pathways, ones that do not involve the androgens or their receptor. Many other growth factors (i.e., epidermal growth factor) and hormones (i.e., prolactin, thyroid, and growth hormones) also are required for maximal development of these tissues. In addition, PCB 169 and TCDD induce many effects that are clearly unrelated to androgen action (eye opening, and female effects like cleft phallus and vaginal threads).

Factors Influencing Estrogen Hydroxylation

There are several factors that have been found to modulate estrogen metabolism. Foodstuffs containing high levels of phytochemicals and indole 3-carbinol found in vegetables like cabbage, cauliflower, Brussels sprouts, broccoli, and kale, increased urinary excretion of 2OHE1 relative to 16aOHE1, through induction of CYP450 2-hydroxylase activity 55 . Exposure to polycyclic aromatic hydrocarbons from cigarette smoking also causes an increase in 2-hydroxylation and this may partly explain the higher risk for osteoporosis in smokers 56 . Medications such as phenobarbital 57 and thyroid hormones may induce 2-hydroxylation 58 , while cimetidine may reduce overall rate of estrogen metabolism 59 . Use of oral contraceptives 60 and increased body weight may significantly lower 2OHE1 16aOHE1 ratio 61 . The lower ratio in overweight individuals is mostly related to a decrease in C-2 hydroxylation, without a change in 16a-hydroxylation 61 . This proestrogenic ratio created by excess body weight

Brain Hormone Synthesis Control

There are several endocrine axes that are controlled by the hypothalamus-pitu-itary regions of the brain, such as the reproductive, growth, thyroid, and stress axes. Within the reproductive axis, gonadotropins from the pituitary, such as gonadotropin II (GtH-II) found in fish, alter steroid hormone production in the gonad 26 . Experimental exposure of feral white sucker fish (Catastomus commer-soni) to bleach kraft mill effluent (BKME) stimulated a 30- to 50-fold decrease in GtH-II concentrations and fish given a synthetic gonadotropin releasing hormone (sGnRH-A) released GtH-II at a significantly lower rate when compared to controls 41 . Further, ovulation in BKME-exposed females did not occur after injection of the GnRH analog as occurred in all control fish. BKME-exposed fish showed a transitory increase in testosterone in response to a sGnRH-A injection, whereas controls had higher concentrations of plasma testosterone and did not respond to treatment with a further elevation 41 ....

The Recombinant DNA Era Today

Thyroid-stimulating hormone 30,500 (TSH) Bovine PTH was used primarily as a diagnostic test to differentiate hypopara-thyroidism from PTH resistance (pseudo-hypoparathyroidism) by measuring urine levels of cyclic adenosine monophosphate before and after PTH injection. As radioimmunoassay techniques for measuring PTH improved, comparing simultaneous serum levels of PTH and calcium permitted the differential diagnosis between the two conditions to be made without the need for sequential urine collections. Direct measurement of PTH by immunoassay of a serum sample is easier for patients and gives more reliable information. Although PTH is no longer used as a diagnostic tool, the availability of recombinant PTH has allowed investigation of its use as a treatment for osteoporosis 15 . duction of recombinant DNA technology. Today recombinant LH and FSH are available for diagnostic use, the treatment of cryptorchidism, and in vitro fertilization. Recombinant DNA-derived thyrotropin...

Liver Hormone Availability

In addition to steroid hormone metabolism, the liver is responsible for another factor that affects the availability of steroid hormones to the cells. Serum binding proteins (SBPs), produced in the liver, transport the lipophilic steroid hormones in the plasma. Examples of SBPs include sex hormone binding globulin (SHBG), corticosteroid and thyroid-retinoic acid hormone binding globulins 27 . Most ( 95 ) of the steroid hormone titer is bound and not free in the plasma, yet only the free fraction of the steroid can produce a biological effect. The bound fraction is thought to function as a storage mechanism for steroid hormones. As long as the hormone is bound to the SBP it is protected from metabolism and excretion 67 . To date, little research has been conducted on the interaction of EDCs with SBPs. Certain contaminants seem to have very low affinity for SBPs. For example, the estrogenic activity of DES, octylphenol, and o,p'-DDT were poorly inhibited by the presence of SHBG or...

Neuroendocrine Alterations

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

Receptors in Brain Gonad and Liver Hormone Action

Action or biological effect of a hormone as well as an EDC are generally thought to depend on that compound binding to its receptor (for a more detailed discussion of contaminant interactions with steroid receptors see 70 ). Larger, more hydrophilic hormones, such as the gonadotropins or adrenocorticotropic hormone, bind to membrane-bound receptors. Steroid hormone receptors belong to the nuclear receptor superfamily,which also includes thyroid hormones, retinoic acid, and vitamin D3 26,27 . These hormones bind to their receptors in the cytoplasm or nucleus of the target cell,where they cause gene transcription (Fig. 2).

Other Hormone Axes and Possible Levels of Disruption

There are other hormone axes similar in structure to the reproductive axis. These include the growth, thyroid, and stress axes (Fig. 3). The proper biological function of each axis depends on the concentration of hormones, whose As members of the nuclear superfamily, reproductive and stress steroid hormone receptors belong to a group of hormones that include thyroid hormones, retinoic acid, and vitamin D3 106 . In the past, these hormones were believed to act strictly as intranuclear transcription regulators. Recent studies have found the existence of membrane bound receptors for estrogens in fish and mammals 32,33,107 . Membrane bound receptors would add another function to the steroid hormone and possibly other members of the nuclear superfamily. In addition to their role as transcription regulators, estrogens acting through membrane receptors and secondary messenger systems could mediate cell activity (enzyme activation inhibition and intracellular ion concentration) (Fig. 2)....

The Substrate Specificity of OATPsOatps

Anions, such as bromosulfophthalein (BSP), bile salts, bilirubin, prostaglandins, and estrogen-conjugates (2) neural steroids and steroid conjugates (3) lipophilic organic cations, e.g., rocuronium and (4) organic dyes, thyroid hormones, and anionic oligopeptides. Various pharmaceutically relevant compounds such as digoxin, pravastatin, methotrexate, temocaprilat, benzylpenicillin, fexofenadine, (D-Pen2, D-Pen5)-enkephalin (DPDPE), as well as some NSAIDs are also substrates of OATP Oatp isoforms (Hagenbuch and Meier, 2003 Tirona and Kim, 2002 Koepsell and Endou, 2004 Sai and Tsuji, 2004) (Table 7.7). The clinical significance of the OATP Oatp family is readily apparent given the wide range of pharmaceutical substrates for its members. The tissue expression patterns and cellular localization of OATP Oatp isoforms (see below), make these transporters attractive targets to enhance drug bioavailability.

Cellular and subcellular localization

In contrast to the H1 -receptor methods, radioligand binding methods for the H2 receptor have been difficult to develop. Radiolabelled cimetidine yielded specific binding, but not to the H2 receptor (Smith etal. 1980), whereas 3H -tiotidine gave an accurate, but low specific binding signal in brain (Gatjkowski etal. 1983). Development of 125I -iodopotentidine permitted identification and characterization of H2 binding sites in guinea pig (Ruat etal. 1990) and primate brain (Martinez-Mir et al. 1990). In both, highest H2 densities were found in caudate, putamen, accumbens, and in some layers of the cerebral cortex. Although a neuronal localization is clear, brain H2 receptors are also found in astrocytes, choroid plexus, and brain microvessel fractions. The H2-receptor activation of adenylate cyclase has been of great value is discerning H2-receptor localization (Johnson 1982). In addition to the well-established existence of these receptors in heart and gastric muscosa, the H2...

Pharmacology and pharmaceutics

Drug interactions According to the product label, a number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. Examples of drugs that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia are oral antidiabetic products, ACE inhibitors, fibrates, fluoxetine, MAO inhibitors, propoxyphene, salicylates, somatostatin analogues (e.g., octreotide), and sulfonamides. Examples of substances that may reduce the blood-glucose-lowering effect of insulin are corticos-teroids, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), isoniazid, and phenothiazine derivatives, somatropin, thyroid hormones, and estrogens, and progestins (e.g., in oral contraceptives). Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. In addition, under the influence of sympatholytic medicinal products such as beta-blockers,...

Steroidogenic Factor

NGFI-B and its related family members Nurr1 and NOR-1 are highly expressed in the adult nervous system, where they are induced as part of the immediate early response to stimuli such as growth factors, membrane depolarization, and seizures (Hazel et al., 1988 Ryseck et al., 1989 Watson and Milbrandt, 1990 Law et al., 1992 Hedvat and Irving, 1995). Their expression outside the nervous system varies significantly among studies, which may reflect the short half-life of NGFI-B transcripts as well as the importance of growth factors in regulating NGFI-B expression (Hazel et al., 1988 Ryseck et al., 1989). In adult rodents, NGFI-B is expressed in the adrenal, thyroid, and pituitary glands, as well as the liver, testis, ovary, thymus, muscle, lung, and ventral prostate (Milbrandt, 1988 Ryseck et al., 1989 Nakai etal., 1990 Lim etal., 1995 Bandoh etal., 1997).Its expression is upregulated in T-cells undergoing apoptosis (Liu et al., 1994 Woronicz et al., 1994). Nurr1 is expressed in the adult...

EPAs Proposed Endocrine Disruptor Screening Program

The Tier 1 screening battery recommended by EDSTAC7 and proposed by the EPA8,9 was the culmination of work begun by other scientific workgroups regarding candidate screening assays for regulatory application.10,11 Prior to EDSTAC, the groups reviewed numerous existing screening assays and concluded that no single assay could detect estrogen, androgen, and thyroid agonists and antagonists. Rather, a battery of in vitro and in vivo assays was thought necessary to evaluate endocrine disruption potential. The former are advantageous in that they are inexpensive and specific for a particular mode of action. Conversely, they lack the metabolic and response complexity of intact animals. After reviewing approximately 80 existing assays, EDSTAC recommended a Tier 1 screening battery consisting of three in vitro and five in vivo assays for Tier The in vivo assays selected for the Tier 1 battery include a rodent 3-day uterotrophic assay, a rodent 20-day pubertal female assay...

Proteinassociated Cns Diseases

While the exact cause of autism is unknown, an abnormal functioning of neurotransmitter receptors may be one mechanism involved. The theory of vaccine-related autism is actually related to the pertussis toxin found in the diphtheria, pertussis, and tetanus (DPT) vaccine. The toxin in the vaccine uncouples Ga proteins from retinoid receptors in the brain, thereby functionally uncoupling receptors from their intracellular signaling proteins (Megson 2000). A pre-existing family history of defects in Ga proteins (night blindness, pseudohypoparathyroidism, and thyroid or pituitary adenoma) increases the risk of autism due to the vaccine.

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

Carbamazepine (CBZ) may be associated with weight gain and metabolic abnormalities, but to a lesser extent than valproate or lithium 95 . In a study of 105 epileptic women treated with valproate and CBZ monotherapy, rates of PCOs were similar (in both groups) to rates in the general population. However, BMI, triglycerides, and postprandial insulin were higher in valproate-treated patients than CBZ-treated patients. Of note, the enzyme-inducing properties of CBZ may reduce levels of free and total thyroxin in patients with thyroid dysfunction 96 . To date, the literature has not supported an association between lamotrigine (LTG) and IR. In a study of 54 women with epilepsy, MetS was more frequently associated with VPA-treated patients (41.7 ) than CBZ (5.3 ), LTG (0 ), or topiramate (TPM) groups (0 ) 97 . A post-hoc analysis was performed from a 12-week prospective open-label study of 1,175 patients with BD initiated on lamotrigine either as monotherapy or adjuvant treatment to...

Pharmacological Effects of Chimeric Peptides

A metabolically stabilized analogue of VIP was constructed which could be biotinylated at a single site. Brain delivery of the biotinylated VIP analogue by the OX26-avidin vector resulted in the desired pharmacological effect. A significant increase in CBF of 65 could be demonstrated after systemic administration of the chimeric peptide. The effect was seen both in anaesthetized rats under controlled respiration after intracarotid infusion as well as in conscious animals after i.v. bolus injection. When an equal dose of the peptide alone without a vector was injected (12 g kg-1 for the intracarotid infusion or 20 g kg-1 in the i.v. study) there was no measurable effect on CBF compared to control animals. In contrast, the well established peripheral effects of VIP on glandular blood flow in the thyroid gland or the sali-

The Expanding Definition of Endocrine Disruption

Originally, the concern over endocrine disruption was based almost entirely on perceived effects on the reproductive system and it was usual to refer to the chemicals concerned as oestrogen mimics or oestrogenic chemicals. Later, chemicals were found that could block oestrogenic responses (anti-oestrogens) or androgenic responses (anti-androgens) and it was soon recognized that chemicals could affect other elements of the endocrine system via interaction with hormone receptors other than those of the sex steroids. The term endocrine disrupter is now preferred because it allows inclusion of health effects thought to result from interference with any part of the endocrine system, including thyroid, thymic and pituitary hormones.

Biochemical Methods To Study Gpcr Oligomerization

Immunoprecipitation has allowed the detection of higher order complexes of several GPCRs, including the thyroid-stimulating hormone (TSH ref. 25) and D2 dopamine receptor (26), suggesting the existence of homodimers and oligomers. Furthermore, studies using native tissues have strengthened the concept that homodimers and oligomers occur in vivo and do not simply result from heterologous overexpression of receptor. Receptor-specific antibodies detected higher order complexes of D3 dopamine receptors in immunoprecipitates from monkey and rat brain (27). Similarly, higher order complexes have been detected in immunoprecipitates prepared from native tissues for the calcium-sensing receptor (28), adenosine A1 receptor (29),

Biosynthesis Of Oligomers Of Gpcrs

Similar detailed studies with GPCRs have not been reported, but there is evidence suggesting that molecular chaperones may participate in GPCR oli-gomeric assembly in the ER. Both the V2 vasopressin receptor and the gona-dotropin-releasing hormone receptor have been shown to form oligomers constitutively (27,32,47) and to interact with calnexin (48,49). The thyrotropin receptor (TSHR) has been reported to interact with BiP (a prototypic Hsp70), calnexin, and calreticulin in the ER (50), and each interaction has unique effects on receptor synthesis and folding. Calnexin and calreticulin appear to stabilize the TSHR and blunt degradation of newly synthesized receptors, whereas association with BiP destabilizes the receptor and promotes proteasomal degradation. As a result, the maturation of TSHR and its ultimate cellular fate is highly dependent on which chaperone system participates in folding after protein synthesis. The TSHR has also been shown to form constitutive oligomers, as...

ABC and SLC Transporters Organic Anion Transporting Polypeptides (OATPs) OATPs are involved in the sodium-independent transport of a diverse range of amphiphilic organic compounds including bile acids, thyroid hormones and steroid conjugates, and many xenobiotics. OATPs can be found in liver, intestine, kidney, and blood-brain barrier. This transporter appears to be involved in clinically relevant transporter drug-drug interactions that are of the largest magnitude.

Side Effects Of Hexaethyltetraphosphate

Hormone(s) (continued) pituitary, 891-894, 892t placental, 895 plasmakinins, 905-906 rDNA-derived, 908t, 910 recombinant, 134-136 somatostatin, 890, 894-895 thyroglobulin, 906 thyroid, 663 thyrotropin, 894 Hormone-related disorders, nonsteroidal therapies for. See Nonsteroidal therapies for hormone-related disorders Hormone replacement therapy (HRT) with androgens, 848-849 combined estrogen progestin, 846-847, 8461 estrogens in, 831 Hormone therapy, for bone disease, 708-710, 709 hPL. See Human placental lactogen HPMPC. See Cidofovir hPTH. See Teriparatide injection HPV. See Human papillomavirus vaccine HRT. See Hormone replacement therapy 5-HT1A antagonists, 515

Importance of Non Monotonic InvertedU Dose Response Curves

Normal development occurs within a limited physiological range for molecules that have a signaling function. For hormones and vitamins that operate via binding to receptors (such as thyroid hormone, vitamin A, and folic acid), either a deficiency or an excess (relative to normal physiological levels) can lead to adverse effects on development 202 . For example, retinoid (vitamin A) deficiency during pregnancy causes fetal death, or if fetuses survive, malformations in numerous organs (the vitamin A-deficiency syndrome) 203, 204 . Studies have also identified birth defects due to developmental exposure to high concentrations of a large number of natural and synthetic retinoids in numerous species 205,206 . Thus, the dose-response curve for vitamin A forms a U-shaped function, with increased risk seen in response to vitamin A deficiency (below the normal range) and excess (above the normal range). The adverse effects of a developmental deficiency as well as a developmental excess of...

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

The Hypothalamus-Pituitary-Thyroid (HPT) Axis, Growth Hormone, Somatostatin, and Prolactin in Depression It has been noted for many decades that many behavioral symptoms of hypothyroidism -dysphoria, anxiety, fatigue, and irritability - overlap those of depression. This observation plus the clinical finding that small doses of thyroid may potentiate the effects of antidepressants (89) has sustained an interest in the relevance of this system to depression. Thyrotropin-releasing hormone (TRH) released from hypothalamus stimulates TRH receptors in the pituitary to release TSH which stimulates specific receptors in the pituitary to release triiodothyroxine (T3) and thyroxine (T4) hormones. A subset of depressed patients show a blunted TSH response to TRH, others symptomless autoimmune thyroiditis (46), and still others an exaggerated

TAM Express Selected M2 Protumoral Function

Cytotoxic Thyroid Cells

The cytokine network expressed at the tumor site plays a central role in the orientation and differentiation of recruited mononuclear phagocytes, thus contributing to direct the local immune system away from antitumor functions (Mantovani et al. 2002). This idea is supported by both preclinical and clinical observations (Bingle et al. 2000 Goerdt and Orfanos 1999) that clearly demonstrate an association between macrophage number density and prognosis in a variety of murine and human malignancies. The immunosuppressive cytokines IL-10 and TGFp are produced by both cancer cells (ovary) and TAM (Mantovani et al. 2002). IL-10 promotes the differentiation of monocytes to mature macrophages and blocks their differentiation to dendritic cells (DC) (Allavena et al. 2000) (Figure 2). Thus, a gradient of tumor-derived IL-10 may account for differentiation along the DC versus the macrophage pathway in different microanatomical localizations in a tumor. Such situation was observed in papillary...

Monocarboxylate Transporters Mct Slc16A

One isoform in the MCT family, MCT10 (TAT1 SLC16A10), is an aromatic amino acid transporter that exhibits proton independent transport of substrates, although it does exhibit 30 identity to other MCTs (Kim et al., 2001a). The high sequence conservation (49 ) between MCT10 and MCT8 suggests MCT8 may not function as a monocarboxylate transporter either (Friesema et al., 2005). Indeed, when expressed in Xenopus oocytes, MCT8 transports thyroid hormones T3 and T4 in a sodium and proton independent manner (Enerson and Drewes, 2003). Neither lactate nor aromatic amino acids appear to be substrates for MCT8 (Enerson and Drewes, 2003). Although the substrate affinities of MCT5-8 have not yet been identified, their similarity to MCT10 may also suggest an alternate substrate affinity, differing from MCT1-4 (Enerson and Drewes, 2003).

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

NRs constitute a large superfamily of intracellular ligand-dependent transcription factors. There are about 50 distinct members in the human genome.28 NRs can be divided into three classes. Cytoplasmic steroid receptors including androgen receptor (AR), mineralcorticoid receptor (MR), estrogen receptor (ER), glucocorticoid receptor (GR) and progesterone receptor (PR) are active as homodimers and undergo nuclear translocation upon ligand binding. The retinoid X receptor (RXR), heterodimeric receptors containing thyroid hormone receptor (TR), vitamin D receptor (VDR) and retinoic acid receptor (RAR) bind the transcription elements as heterodimers with RXR and are retained in the nucleus regardless of the presence of ligands.29,30 NRs share six common functional and structural domains including a variable A B amino-terminal region (50-500 amino acids) a highly conserved C domain ( 70-80 amino acids) responsible for specific binding of the receptor to its target...

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...

Xray Crystallography And Steroid Fit At The Receptor

The x-ray crystal structures of the steroid hormones themselves have also provided important information. Although the conformations of rigid molecules in crystals and their preferred conformations in solution with receptors can differ, it is now clear from x-ray crystallography studies of steroids, prostaglandins, thyroid compounds, and many other drug classes that this technique can be a powerful tool in understanding drug action and in designing new drugs.27-29 The relationship is straightforward steroid drugs usually do not have a charge and, as a result, are held to their receptors by relatively weak forces of attraction. The same is true for steroid molecules as they pack into crystals. In both events, the binding energy is too small to hold any but low-energy conformations. In short, the steroid conformation observed in steroid crystals is often the same or very similar to that at the receptor.

Meeting The Objectives Of Nonclincal Studies

There is evidence, however, demonstrating that many compounds found to be carcinogenic in rodent bioassays are likely not to be human carcinogens 6 . For this reason, much effort is placed on understanding and interpretation of rodent carcinogenicity study findings, and more recently on evaluating alternative transgenic models for improving the science of carcinogenicity testing 7 . In this regard, evaluations of the human relevancy of certain animal tumor findings have been investigated through well-designed follow-up mechanistic animal studies incorporating biomarker analyses (Table 2). In such cases, dose-dependent tumorigenesis can be linked to the same dose-dependent alteration in mechanistically linked biomarker alterations, and intervention of biomarker-dependent mechanisms can often be demonstrated to block tumor induction. Findings may be judged to be of little relevance to humans if the mechanism is specific for rodents, or if the doses associated with...

More Products

The Natural Thyroid Diet

Download Thyroid Factor Now

Thyroid Factor is not for free and currently there is no free download offered by the author.

Download Now