What are chemical messengers that diffuse through tissue fluid and affect only nearby cells called?

Extracellular Regulation: Microbial, Autocrine, Luminal, Paracrine, Immunologic, Neural, and Endocrine Systems (Malpines)

The complex minute-by-minute regulation of intestinal function is achieved by the intricate coordination of extracellular factors, contributed by the intestinal microbial, autocrine, luminal, paracrine, immunologic, neural, and endocrine systems (MALPINES). Originally restricted to “PINES,” this definition has been expanded, and although the distinctions between individual regulatory systems are getting blurred because of the considerable and differential crosstalk of the underlying pathways in health and disease states, the nomenclature is nevertheless useful (Fig. 101.11). These interactions are compounded by factors with overlapping actions, many of them acting through cell-specific multiple receptors linked to varied signaling pathways.

The last decade has seen an explosion of information on the influence of the luminal microbiome in health and disease states (Chapter 3) ranging from traditional infectious diarrheas, includingClostridioides difficile infection (Chapter 112) to obesity (Chapters 7Chapter 7Chapter 8 and8Chapter 7Chapter 8) and amyotropic lateral sclerosis. In addition, luminal mechanical (stroking and stretch) or chemical (toxins) stimuli can activate mechanoreceptors and chemoreceptors, respectively, to in turn activate one or more arms of ALPINES. Within the subepithelium, structural elements of ALPINES, including blood vessels, are in close proximity (seeFig. 101.11), so release of mast cell mediators can easily target neurons and vice versa; this interplay is critical for the minute-by-minute local regulation necessary in the intestine. Although it is possible to define the specific effects of an individual component in-vitro, clinically the regulatory systems are inextricably intertwined. For example, Verner-Morrison syndrome (pancreatic cholera) is classified as an endocrine-mediated diarrhea because pancreatic islet cell tumors produce large amounts of vasoactive intestinal peptide (VIP) (seeChapter 34). In the healthy adult, however, VIP is not found in the pancreas but is a peptidergic neurotransmitter of the enteric nervous system (ENS) that stimulates epithelial cell secretion and smooth muscle relaxation. In another example, serotonin (5-hydroxytryptamine [5-HT]) is released from mucosal enterochromaffin cells either directly or indirectly by a variety of mechanical, microbial and chemical stimuli, after which it acts via distinct receptors to elicit a plethora of actions ranging from pro-inflammatory to neuroprotective231: on enterocytes to directly stimulate secretion; on myenteric neurons to release acetylcholine (ACh) and elicit migratory contractions; on submucosal neurons to release ACh and calcitonin gene-related peptide to stimulate peristalsis and secretory reflexes; its receptor expression, and therefore function, is influenced by the microbiome.124,125

Conclusions

The endocrine system regulates the complexity of the Life expressing itself in an organized fashion. The endocrine system’s regulation of itself and its calibration by other factors is similarly complex. This ensures a high degree of responsiveness and attunement of metabolic demands to the requirements of the organism. In addition to the classical definition of hormones by location of origin and distance of action, we presented the Endobiogenic notion of hormone function by type of metabolism regulated. A new system of classification of hormones based on both the geometric and political notions of axis were presented, allowing for an expansion of classification of hormones based on complementarity of action rather than vertical control mechanisms. With this notion of association arises the notion of endocrine axial associations, and new concepts of regulation: horizontal and radial. The organization of the endocrine system in this fashion, while conceptual provides a sense of coherence to the notion of how the terrain is managed. For the clinician, it forms the basis of explaining the origins of disorders and dysfunctions, and will provide the foundation for the selection of a rational selection of therapeutic interventions.

Neuroendocrine integration: Adaptation states

The endocrine system is the manager of the terrain, but the ANS regulates the endocrine system’s management of the terrain. It is the permanent and dynamic interaction of neuroendocrine activity that ultimately assures the proper regulation of metabolism and survival of the organism (Fig. 2.14). Thus, in practical terms, it is the neuroendocrine system that regulates the terrain. We briefly summarize three general types of functional capacity through neuroendocrine activity (cf. Chapter 6 for more details):

Basal capacity: Basal metabolic function for the maintenance of structure and function of structure.

Adaptation syndromes: A series of normal physiologic reactions that install a change in the functional equilibrium and which result in a return to the prior state once the demand is resolved.

Adaptability: A state of physiologic function that is contrary to a person’s optimal physiology. It can serve as a method of economizing adaptation syndromes by maintaining the minimum number of elements of the terrain in an altered physiologic state in order to allow the remaining elements of the terrain to return to their prior state. Hashimoto’s thyroiditis is an example of adaptability.

Contribution of the Autonomic Nervous System to Endocrine Control

Another major precept of neuroendocrinology is that the nervous system controls or modifies the function of both endocrine and exocrine glands. The exquisite control of the anterior pituitary gland is accomplished by the action of releasing-factor hormones (see “Hypophysiotropic Hormones and Neuroendocrine Axes”). Other endocrine and exocrine organs (e.g., pancreas and adrenal, pineal, and salivary glands) are also regulated through direct innervation from the cholinergic and noradrenergic inputs from the autonomic nervous system. An appreciation of the functional anatomy and pharmacology of the parasympathetic and sympathetic nervous systems is fundamental in understanding the neural control of endocrine function.20

The efferent arms of the autonomic nervous system comprise the sympathetic and parasympathetic systems. They have similar wiring diagrams characterized by a preganglionic neuron that innervates a postganglionic neuron that, in turn, targets an end organ.21 Preganglionic and postganglionic parasympathetic neurons are cholinergic. In contrast, preganglionic sympathetic neurons are cholinergic, and postganglionic neurons are noradrenergic (except for those innervating sweat glands, which are cholinergic). Another basic concept is that autonomic neurons coexpress several neuropeptides. This coexpression is a common feature of neurons in the central and peripheral nervous systems.18 For example, postganglionic noradrenergic neurons can coexpress somatostatin and neuropeptide Y (NPY), whereas postganglionic cholinergic neurons can coexpress vasoactive intestinal polypeptide (VIP) and calcitonin gene–related peptide (CGRP).

Most sympathetic preganglionic neurons lie in the intermediolateral cell column in the thoracolumbar regions of the spinal cord.21 Most postganglionic neurons are located in sympathetic ganglia lying near the vertebral column (e.g., sympathetic chain and superior cervical ganglia). Postganglionic fibers innervate target organs. As a rule, sympathetic preganglionic fibers are relatively short and the postganglionic fibers are long. In contrast, the parasympathetic preganglionic neurons lie in the midbrain (perioculomotor area, long misidentified as the Edinger-Westphal nucleus22), the medulla oblongata (e.g., dorsal motor nucleus of the vagus and nucleus ambiguus), and the sacral spinal cord. Postganglionic neurons that innervate the eye and salivary glands arise from the ciliary, pterygopalatine, submandibular, and otic ganglia. Postganglionic parasympathetic neurons in the thorax and abdomen typically lie within the target organs, including the gut wall and pancreas.21 Consequently, the parasympathetic preganglionic fibers are relatively long and the postganglionic fibers are short.

The dual autonomic innervation of the pancreas illustrates the importance of coordinated neural control of endocrine organs. The endocrine pancreas receives sympathetic (noradrenergic) and parasympathetic (cholinergic) innervation.21,23 The latter activity is provided by the vagus nerve (dorsal motor nucleus of the vagus) and is an excellent example of neural modulation because the cholinergic tone of the beta cells affects their secretion of insulin. For example, vagal input is thought to modulate insulin secretion before (cephalic phase), during, and after ingestion of food.24 In addition, noradrenergic stimulation of the endocrine pancreas can alter the secretion of glucagon and inhibit insulin release.23 Of course, a major regulator of insulin secretion is the extracellular concentration of glucose,25 and glucose can induce insulin secretion in the absence of neural input. However, the exquisite control by the nervous system is illustrated by the fact that populations of neurons in the hypothalamus, including ventromedial and perifornical hypothalamic neurons, and catecholamine neurons in the rostral ventral lateral medulla of the brainstem, like the pancreatic beta cell, have the ability to sense glucose levels in the bloodstream.26 This information is particularly important to initiate counterregulatory responses to prevent hypoglycemia by altering the activity of the autonomic nervous system innervating the pancreas and adrenal glands while simultaneously facilitating arousal through projections to histaminergic neurons in the tuberomammillary nucleus (TMN) and inducing feeding responses.27,28

Introduction

The endocrine system regulates metabolism. How one line of endocrine activity calibrates or affects another has been discussed Chapter 10. This chapter focuses on how the endocrine system affects organs. Endocrine demand solicits organs to do something. The targeted organ(s) may serve one or more of the following roles: (1) intake, (2) uptake, (3) processing, (4) excretion, (5) detoxification, (6) growth, or (7) production. For example, when ACTH stimulates the adrenal gland to produce aldosterone (#7), it anticipates that aldosterone will affect electrolyte and water balance. To accommodate that, ACTH also stimulates the colon (#4) to reabsorb electrolytes and water from stool that aldosterone will require for its actions. During the adaptation response, FSH stimulates the ovaries (#7) to produce estrogens for the construction of immune factors. The FSH solicits the colon (#4) to absorb more proteins, and estrogens solicit the liver (#7) to produce immune factors. However, the liver is at risk of being congested, impairing its detoxification of the blood (#5) and its management of nutrients through portal circulation (#3).

Each axis has its particular organs that it solicits for various functions (Chapter 2). Prolonged or intense solicitation diminishes buffering capacity and adaptability (Fig. 11.1). When the organ solicited cannot keep up with the demands imposed by the endocrine system it can become congested. In determine that can affect drainage or detoxification. These dysfunctions are implicated in precritical and critical terrains of every disorder, according to the theory of Endobiogeny (cf. The theory of Endobiogeny, Volumes 2–4).

Abstract

The endocrine system works along with the nervous system to regulate the functions of the human body to maintain homeostasis. However, the endocrine system works much more slowly than the nervous system, which can cause responses to occur within milliseconds. The endocrine system and its widely scattered glands secrete hormones that diffuse from the interstitial fluid into the bloodstream. The hormones, which are chemical messengers, act on target cells, regulating their metabolic functions. Hormones affect most body cells, regulating growth and development, balance of blood components, body defenses, cellular metabolism, energy balance, and even reproduction. Hormones are considered “long-distance” chemical signals. However, there are also “short-distance” chemical signals: the paracrines and autocrines. Paracrine secretions are those that affect only neighboring cells. An example of paracrine actions is when somatostatin from the pancreatic cells known as D cells stops insulin release by pancreatic B cells. Autocrine secretions are those that affect the secreting cell only, such as the prostaglandins that are released by smooth muscle cells and cause contraction of these cells. Exocrine glands are those that secrete nonhormonal substances outside the body through ducts and include the sweat and salivary glands. The endocrine system controls body processes for long periods of time.

Effects on the Endocrine Systems

Endocrine systems play roles in a variety of hormonal interactions that have an impact on a range of biologic processes such as sexual maturity and regulation of metabolism. Some studies of fluoride exposure in drinking water at levels below 4 mg/L have demonstrated associations between fluoride level and thyroid function. However, the changes observed in thyroid function are not linked to an adverse health condition. For example, calcitonin and parathyroid hormone levels may be observed to be higher in individuals exposed to fluoride, but normal physiologic functions are not impaired. Most studies of the impact of fluoride exposure on the endocrine system are primarily focused on thyroid function. Two recent studies are described here.

One is an ecologic study from the United Kingdom,58 and the other is a cross-sectional study from Canada.4 Both had limitations, but the ecologic design is inferior in that the exposure—fluoride in this case—is not measured at the level of the individual. The Canadian study4 had good measures of exposure at the level of individual, but being a cross-sectional study, the exposure only reflected the current level fluoride and did not provide longitudinal exposure history, although the study participants did provide residence histories going back 3 years so that exposure histories could be constructed. The cross-sectional design is a limitation. However, the study did make use of a population-based sample that is representative of the Canadian population. It showed no association between fluoride level and thyroid stimulating hormone or self-reported thyroid disorders. In addition to residence histories for the past 3 years, tap water samples and urine samples from study participants were used to assess fluoride exposure. The study provides good evidence that at the level of the individual, fluoride exposure at levels common to the general population does not impair thyroid function.

In 2015 researchers from England conducted an ecologic study that looked at the association between locations with fluoridated water and prevalence of hypothyroidism from a registry kept by the national health system.58 The data showed an association between diagnosis of hypothyroidism and living in an area where public water is fluoridated. The authors note that only 10% of the population has exposure to public water systems that are fluoridated. This raises concerns that people living in communities that fluoridate the water may also differ in other ways from the 90% of the people living in other nonfluoride communities.

The thyroid gland is of importance to fluoride safety largely because we know that fluoride (fluorine) and iodine have similar chemical properties, and iodine is clearly linked to healthy thyroid function. The two studies that were published since the NRC report each had limitations, and taken together they did not demonstrate any adverse health outcomes attributable to fluoride.

OVERVIEW

Fetal endocrine systems can be classified as shown in Table 145-2. The neuroendocrine hormone systems transduce or convert neural into endocrine information. These include the hypothalamic–anterior pituitary system, the hypothalamic–posterior pituitary system, and the autonomic nervous system. The insulin-glucagon and parathyroid hormone–calcitonin systems function autonomously, with hormone secretion regulated largely by local feedback mechanisms. The events of parturition abruptly terminate the period of protected fetal development and precipitate a series of profound metabolic stresses. The neuroendocrine transducer systems are well developed at birth and function smoothly to defend against these stresses. The autonomous endocrine systems regulating blood sugar and calcium levels, however, are relatively suppressed in utero and must adapt rapidly to the extrauterine environment. Abnormalities related to homeostasis of blood sugar and serum calcium concentrations are relatively frequent in the early neonatal period.

5.4 Conclusions

The thyroid hormonal system has wide-ranging effects on intermediary metabolism, the cardiovascular system, energy intake, and thermogenesis in mammals. Normal levels of thyroid hormones are also critical for brain and skeletal development in the developing young. Disruption of the thyroid hormonal system may have many consequences for human health and effects monitored to date include lowered IQ and altered neurological development. There are several in vivo tests in experimental animals that detect disruption of the thyroid hormonal system by determining thyroid-related hormone levels and effects on the thyroid gland itself. However, the complexity of the thyroid hormonal system and the diversity of potential ways in which it may be disrupted mean that validation of in vitro tests has been slow. However, current activities are addressing in vitro tests for molecular targets involved in thyroid hormone synthesis, transport, receptor binding, and metabolism. The validation of new tests and the development of AOPs for thyroid disruption should facilitate progress in this area of science and risk assessment.