Endocrine systems

The endocrine system can be broadly described as an assemblage of organs (glands) that produce chemical messengers (hormones) that regulate various bodily functions. The bodily functions regulated by the endocrine system can be categorized as those 

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley Sons, Inc. 

Hormone Group Example Origin Regulated Process 

Androgens Testosterone Testes, adrenals Sexual differentiation, fertility, secondary sex characteristics, sexual function, libido 

The endocrine system is comprised of a network of hormone-producing glands that synthesize and release carefully measured doses of these hormones, which in some instances are in the parts per trillion range. Insufficient as well as excessive quantities of these hormones can be detrimental to one s health and well-being. As discussed in Section 4.11, endocrine disrupting compounds (EDCs) are exogenous chemicals that alter the function of the endocrine system by one of four different ways  

Acting as hormone mimics, that is, attaching themselves to hormone receptor sites and mimicking the effects of endogenous hormones. 

Disrupting the synthesis and metabolism of endogenous hormone receptors. 

5 Mixture Effects on Endocrine Function Case Studies 

Human Toxicology of Chemical Mixtures. DOI 10.1016/B978-1-4377-3463-8.00022-9 2011 Elsevier Inc, All rights reserved. 

The primary purpose of the endocrine system is to maintain homeostasis — that is, to maintain a relatively constant internal environment in the face of a constantly changing external environment. The endocrine system consists of hormones and the glands and tissues that produce the hormones. A hormone is a chemical substance released by certain cells to effect the function of other distant cells (endocrine function). Many compounds act as endocrine hormones as well as having paracrine and autocrine functions. Paracrine and autocrine describe actions on nearby cells and on other cells that produce the substance, respectively. There is considerable overlap between substances classified as hormones and other chemical messengers such as neurotransmitters and cytokines. Many substances function in more than one of these categories. For example, epinephrine and norepinephrine function as both neurotransmitters and adrenal medullary hormones. 

Li+ has been reported to affect virtually every component of the endocrine system to some extent however any resulting clinical manifestations are very rare [169]. Although these influences do not appear to be related to its mechanism of action in manic-depression, some are involved in the side effects experienced by Li+-treated patients. Apart from elevated levels of thyroid stimulating hormone (TSH), Li+ does not appear to affect the basal levels of hormones significantly however some hormone responses are reported to be altered by Li+ treatment of bipolar patients [170]. Neuronal activity stimulates the adrenal medulla to release norepinephrine and epinephrine into the blood and, consequently, the plasma from people with mania and depression shows increased levels of both neurotransmitters [171]. 

Li+ has variable effects upon all hormones released by the pituitary, either directly or indirectly, and in some cases the effects are equivocal. 

The response of prolactin (PRL) to the hypothalamic TSH-releasing hormone (TRH) and to insulin hypoglycemia is reduced in long-term Li+-treated patients, as is the response of growth hormone to insulin hypoglycemia however the concentration of growth hormone is also reported to be elevated during Li+ treatment [170]. 

The observed Li+-induced stimulation of corticotropin (ACTH) secretion from cells in culture, requiring extracellular Ca2+, involves a corresponding and apparently associated increase in the concentration of Ins(l)P, indicating some interaction with phosphoinositide metabolism [176], Pretreatment with Li+ desensitizes the cells, reducing this Li+-induced stimulation of ACTH secretion. Li+ initially raises plasma cortisol levels in manic-depressives however the levels are subsequently reduced with chronic Li+ treatment in both patients and controls [177]. This effect is probably secondary to the stimulation and subsequent desensitization of ACTH secretion by Li+, as observed in cultured cells. 

Reports of the effects of Li+ upon the thyroid gland and its associated hormones are the most abundant of those concerned with the endocrine system. Li+ inhibits thyroid hormone release, leading to reduced levels of circulating hormone, in both psychiatric patients and healthy controls [178]. In consequence of this, a negative feedback mechanism increases the production of pituitary TSH. Li+ also causes an increase in hypothalamic thyroid-releasing hormone (TRH), probably by inhibiting its re- 

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L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Interaction of vitamin D and its metaboUtes with sex hormones has been demonstrated, particularly ia birds ia which the egg-laying functions combine calcium needs and reproductive activity. The metaboUtes of vitamin D behave as hormones. As such, they play an active role ia the endocrine system, along with other hormones, to maintain the various body functions. Several biological influences of metaboUtes of vitamin D have been studied, including effects related to cancer (193—197), skin diseases (198—201), immunomodulatory effects (202,203), and Alzheimer s disease (204—206) (Fig. 9). 

A second problem concerns delimiting the mechanisms of action which should be included in the definition, to exclude effects which are a secondary consequence of overt toxicity in other body systems. For example, disruption to the endocrine system caused by general metabolic disturbance, such as in severe liver damage, should not be grounds for calling a chemical an ED. 

There are many possible mechanisms by which chemicals may interact with the endocrine system, some of which are discussed below. 

Many different test systems have been used to investigate the ability of chemicals to interact with components of the endocrine system. The usefulness and applicability of the available methods has been the subject of much debate. Four key texts are particularly helpful in reviewing and giving guidance on currently available test methods and strategies for testing EDs. ... 

Tier 2 is intended to determine and characterize the effects of the chemical on the endocrine system and includes ... 

Figure 1 A schematic diagram of the endocrine system of fish. TRH = thyrotrophin releasing hormone GnRH = gonadotrophin releasing hormone CRH = corticotrophin releasing hormone TSH = thyroid stimulating hormone GtH = gonadotrophins I and II ...

The liver plays an important role in the endocrine system. The concentrations of hormones in plasma, and the activity of the glands which secrete them, are determined by the rate at which they are deactivated by the liver. The liver also has a major function in female reproduction since it is the target tissue of ovarian estrogen, to which it responds by producing the yolk protein vitellogenin. " Xenobiotics that affect either of these functions can therefore be considered to be potential endocrine disrupters. 

Fish have many advantages as experimental models in the study of endocrine disruption, and although they do have some significant differences in their endocrine system to that of mammals, the underlying basis is very similar. Chemicals which are shown to be either actual or potential endocrine disrupters... 

Capen, C. C. (1996). Toxic responses of the endocrine system. Jn Casarett and DouU s Toxicology The Baste Science, of Poisons (C. D. Klaassen, Ed. , pp. 617-640. McGraw-Hill, New York. 

The cytokine leptin is secreted by adipocytes (fat cells) in proportion to the size of the adipose dq>ot and circulates via the bloodstream to the brain, where it ultimately affects feeding behavior, endocrine systems including reproductive function and, at least in rodents, energy expenditure. The major effect of Lqrtin is on the hy-pothalamous, where it suppresses appetite and hence food intake. Leptin exerts its effects via binding to the leptin receptor in the brain (specifically in the hypothalamus), which activates the JAK-STAT Pathway. 

UNIT IX Drugs That Affect the Endocrine System... 

Endocrine system—menstrual irregularities, hyperglycemia, and decreased growth in children and... 

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