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How cells communicate, part I: The neuroendocrine system and feedback.

The traditional motto of the United States of America is E pluribus unum, which means "out of many, one." Likewise, each human body is made up of trillions of cells, each of which is an organism in its own right. Yet the human body can function as a single organism because of how these trillions of cells work together. This cooperation is possible because cells have ways of communicating with each other. This 3-part series will provide an overview of how cells within the human body communicate with each other in health and disease, and how medications can alter these communications. This first part introduces the neuroendocrine system and describes feedback loops.

THE DISCOVERY OF ENDOCRINE GLANDS

Ancient people knew that the testes had powerful effects on the body. Males who had lost their testes in childhood would never go through puberty. They retained their high voices, and they never grew a beard. Nor did they go bald. They also tended to grow abnormally tall. Yet nobody knew how the testes could exert their effects on the rest of the body.

Ancient people knew that some organs (eg, oil glands, sweat glands, and mammary glands) could release substances from the body through a tube called a duct. The glands that release their products through a duct are called exocrine glands. During the Renaissance, anatomists started to suspect that some organs besides the testes were secreting something into the body, even though those organs had no visible ducts. Besides the testes and ovaries, these ductless glands included the adrenals, thyroid, thymus, and spleen. The mystery of how the secretions of the ductless glands could be delivered to distant sites in the body was solved in 1628, when William Harvey suggested that blood circulates--traveling from the heart, to the rest of the body, and then back to the heart. (1) Substances that enter the bloodstream at any point could thus be carried to the rest of the body.

The glands that release substances directly into the bloodstream are called ductless or endocrine glands (Figure 1).

[FIGURE 1 OMITTED]

HOMEOSTASIS

In 1855, Claude Bernard discovered that the liver could secrete glucose into the hepatic vein. Thus, the liver could supply glucose to the bloodstream, even if the person had not eaten any sugar or starch recently. (2) As such, the liver played an important role in maintaining normal blood glucose levels. Bernard argued that the human body cannot survive unless it can maintain the internal environment (milieu interieur) around its cells. For example, abnormally high or low body temperature, blood pH, or blood sugar would be fatal. In 1926, Walter B. Cannon referred to the body's process of maintaining this steady internal environment as homeostasis, a word that implies "staying the same." (3)

The body has many homeostatic systems. Disorders of these homeostatic systems can result in sickness or death. Also, many drugs have effects on one or more of the body's homeostatic systems. These systems typically operate through a process of direct influence and feedback. The set of direct influences and feedback interactions among a set of endocrine glands is often called an axis (eg, the hypothalamic-pituitary-thyroid axis).

THE HYPOTHALAMIC-PITUITARY-THYROID AXIS

The thyroid is a butterfly-shaped gland in the neck, just below the laryngeal prominence (Adam's apple). The thyroid produces 2 hormones (thyroxine [[T.sub.4], which contains 4 iodine atoms] and tri-iodothyronine [[T.sub.3], which contains 3 iodine atoms]) that influence the rate of the body's metabolic processes. These hormones stimulate the basal metabolic rate: body temperature rises, the heart beats harder and faster, stored nutrients are released from the liver and muscles, and stimulation of the nervous system leads to higher levels of attention and quicker reflexes. In children, the thyroid hormones promote brain development as well as growth. (4)

The balance of thyroid hormone levels is critically important because too much is bad, and too little is bad, but normal homeostatic levels are just right. In healthy people, the production of [T.sub.3] and [T.sub.4] by the thyroid is controlled by the hypothalamic-pituitary-thyroid axis (5) (Figure 2). When the amount of [T.sub.3] and [T.sub.4] in circulation is low, the hypothalamus releases a hormone called thyrotropin-releasing hormone (TRH) into the hypophyseal portal system (Figure 2, inset), which is a system of blood vessels that carries blood from the hypothalamus to the anterior pituitary gland. In response to the TRH, some cells in the anterior pituitary release thyrotropin, which is also called thyroid-stimulating hormone (TSH), into the bloodstream. The bloodstream then carries TSH all over the body. In the thyroid, the TSH promotes the release of [T.sub.4] and (to a lesser degree) [T.sub.3]. Some of the [T.sub.4] will then be converted to [T.sub.3] in other tissues, such as skeletal muscle. This conversion of [T.sub.4] to [T.sub.3] is influenced by many different hormones (including TSH and adrenal hormones), as well as by nerve signals.

In a healthy person, the hypothalamic-pituitary-thyroid axis keeps [T.sub.4] and [T.sub.3] levels from falling too low or rising too high. Low [T.sub.4] and [T.sub.3] levels promote the release of TRH, which stimulates the release of TSH, which further promotes the release of [T.sub.4] and [T.sub.3]. Adequate or high levels of [T.sub.4] and [T.sub.3] then suppress the release of TRH and TSH. Without TRH, the pituitary does not produce much TSH. Without TSH, a healthy thyroid does not produce much [T.sub.4] or [T.sub.3]. (5)

The [T.sub.4] and [T.sub.3] are outputs of the system. However, because of their influence on the hypothalamus, they should also be regarded as inputs to the system. This process of outputs becoming inputs is called feedback. [T.sub.4] and [T.sub.3] suppress the processes that lead to their secretion. This kind of suppression is called negative feedback. Many homeostatic systems involve negative feedback loops. However, some hormones can have positive feedback effects under certain circumstances. For example, before ovulation, estrogen has a positive feedback effect on the hypothalamus and pituitary. The estrogen produced by the ovary then promotes the release of gonadotropin-releasing hormone, which stimulates the release of luteinizing hormone, which then promotes the release of more estrogen by the ovary. (6)

[FIGURE 2 OMITTED]

THYROID DISORDERS

If something goes wrong in any portion of the hypothalamic-pituitary-thyroid axis, thyroid hormone levels could be too low (hypothyroidism) (7) or too high (hyperthyroidism). (8)

Hypothyroidism could be caused by a problem with the thyroid gland (eg, because of thyroid surgery or autoimmune thyroiditis). It can also result from a lack of TSH because of failure of the anterior pituitary. It can even be the result of some problems involving the hypothalamus. For example, disruption of the hypophyseal portal vein would prevent TRH from being carried to the anterior pituitary. Also, starvation or other serious illness may cause the hypothalamus to alter the set point of thyroid homeostasis. (9)

Hyperthyroidism usually results from a problem in the thyroid gland. However, it can also result from a TSH-secreting tumor of the pituitary. Abnormally high [T.sub.4] can also occur from eating animal thyroid tissue or from taking an overdose of thyroid replacement pills. (8)

The first step in diagnosing a disorder of the hypothalamic-pituitary-thyroid axis is to measure the blood levels of [T.sub.4] and [T.sub.3] and TSH. (10) If the thyroid cannot produce enough thyroid hormone, [T.sub.4] and [T.sub.3] levels will be low but TSH will be high, as the hypothalamus and pituitary try to correct the problem. If the problem is in the hypothalamus or pituitary, TSH levels will be low. In cases of hyperthyroidism, the TSH will be low if the problem results from overactive thyroid tissue but high if the problem is a TSH-secreting pituitary adenoma.

NEUROENDOCRINE SIGNALING

The hypothalamic-pituitary-thyroid axis is just one example of a neuroendocrine regulatory system, involving both nerve and endocrine tissues. There are many other neuroendocrine regulatory systems in the body. Often, these systems interact with each other in complicated ways. Yet there are some general principles that can provide a basic context; they deal with the location, specificity, and timing of the signaling.

Location

As stated previously, endocrine glands release substances directly into the bloodstream. Those substances--hormones--are signaling compounds that are released into the bloodstream and that carry a signal to some distant target tissue. This distance is important: you cannot regulate the temperature of your house by putting your thermostat inside your furnace. The thermostat must be distant from the furnace, so that it can measure the effects that the furnace is having in the living areas of the house. Likewise, many bodily processes are regulated by hormones released by endocrine tissue that is distant from the process in question. For example, the storage or production of glucose by the liver is regulated by hormones produced by the pancreas. (11) Likewise, the uptake of iron from the intestine is regulated by a hormone produced by the liver. (12)

Specificity

A signaling system must provide a signal to the target cells, but not to other cells. There are 3 basic ways to achieve this specificity. One is through nerves, whereby a nerve fiber provides a specific signal to a highly specific area of tissue. Another way is through a vascular structure (eg, the hypophyseal portal vein carries small doses of hormones from the hypothalamus directly to the pituitary). The third way to achieve specificity is through the selectivity of receptors on or in the cells of the target tissue. The presence of these receptors on or in some cells, but not others, explains why a hormone can have effects on some cells, but not others. Differences in how the subtypes of the receptors for that hormone are connected to the cell's internal signaling systems explain how the same hormone can have different effects on different kinds of cells.

Timing

For a signaling system to be useful, the signal has to turn on and off in a timely manner. Neurotransmission (13) is the fastest kind of signaling in the body. Nerve cells pass signals to each other by releasing chemicals called neurotransmitters into the synapse (gap) between cells. These neurotransmitters have an immediate effect. The signal is then stopped as the neurotransmitter is removed from the gap, either by reuptake, diffusion, or degradation. Reuptake means that a transporter brings the neurotransmitter into a cell. Diffusion happens when the substance simply drifts away. Degradation means that the substance is broken down (eg, by an enzyme). Because of these processes, the neurotransmitter may remain in the synapse for only a fraction of a second. The resulting neural signal thus has a rapid onset and a short duration.

Many homeostatic mechanisms, such as those affecting blood sugar levels, do not require split-second timing. However, they often need to exert an effect within a matter of minutes to maintain control over vital systems. Many of the hormones involved in these systems are called peptide hormones because they are made out of small chains of amino acids (typically fewer than 50-100 amino acids). These peptide hormones (eg, insulin and vasopressin) tend to have a half-life of 10 to 20 minutes. (14,15) In other words, half of the biological effect of that hormone is lost by 10 to 20 minutes after secretion.

Some hormones (eg, follicle-stimulating hormone and luteinizing hormone) are glycoproteins, which means that they are proteins that also have sugar molecules attached. They tend to have a slightly longer half-life (eg, 3 to 4 hours for follicle-stimulating hormone). (16)

The sex glands and the adrenal glands make several steroid hormones, including corticosteroids. The steroid hormones are fat-soluble compounds that are derived from cholesterol. They tend to have a longer half-life (eg, estradiol has a half-life of approximately 13 to 20 hours). (17)

TREATMENT OF ENDOCRINE DISORDERS

Many endocrine diseases result from the over- or underproduction of some hormone. The overproduction of a hormone is often due to a functional tumor, which can often be removed surgically. Other ablative methods can also be used, such as when hyperthyroidism is treated by giving a dose of radioactive iodine, which is taken up by and destroys thyroid tissue. (18) The patient will then require hormone replacement therapy.

The underproduction of a hormone is often treated by hormone replacement. The protein (eg, insulin) and glycoprotein hormones (eg, follicle-stimulating hormone) generally have to be administered by injection because they would be digested in the stomach if administered orally. (19,20) One exception is desmopressin, which is a peptide hormone that can be administered orally or intranasally. (21) Steroid hormones also can be administered orally, although a portion of the oral dose will be broken down in the liver before it reaches the general circulation). (22)

Sometimes, drugs with hormone-like effects are used for purposes other than hormone replacement. For example, drugs with effects that mimic the glucocorticoid hormones produced by the adrenal glands are often used for their anti-inflammatory effects. (23)

The effect of a hormone drug on the body's hormonal balance can be hard to predict because the drug can have effects on various feedback loops. For example, administration of glucocorticoid drugs tends to suppress the production of corticotropin-releasing hormone by the hypothalamus, thus suppressing the release of corticotropin by the pituitary, which leads to suppression of the release of cortisol by the adrenal glands. (24) For this reason, glucocorticoid drugs should not be abruptly stopped. Instead, they should be tapered, to allow the hypothalamic-pituitary-adrenal axis to return to normal. (23)

CONCLUSION

In a healthy person, the endocrine glands interact with each other in complicated ways to promote growth, maintenance, and reproduction. Disorders of the endocrine glands can therefore have complicated effects on the body. Medications with hormone-like effects are often used to treat endocrine disease and for other purposes. Hormones, neurotransmitters, and other signaling molecules exert their effects on target tissues by binding to receptors that are on (or sometimes in) the target cells. Part 2 of this series will discuss the relationships between these signaling molecules and their receptors.

References

(1.) Rodin FH. The lure of medical history: William Harvey: Part II: De Motu Cordis. Cal West Med. 1929;30(1):43-44.

(2.) McGarry JD, Kuwajima M, Newgard CB, Foster DW, Katz J. From dietary glucose to liver glycogen: the full circle round. Annu Rev Nutr. 1987; 7:51-73.

(3.) Brown TM, Fee E. Walter Bradford Cannon: pioneer physiologist of human emotions. Am J Public Health. 2002;92(10):1594-1595.

(4.) Online IH. How does the thyroid work? PubMed Health website. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072572/. Updated January 7, 2015.

(5.) Mariotti S, Beck-Peccoz P. Physiology of the hypothalamic-pituitary-thyroid axis. Thyroid Disease Manager website. http://www.thyroidmanager.org/chapter/physiology-of-the-hypothalamic-pituitary-thyroid-axis/. Updated August 14, 2016.

(6.) Micevych P, Sinchak K. The neurosteroid progesterone underlies estrogen positive feedback of the LH surge. Front Endocrinol (Lausanne). 2011;2:90.

(7.) Wiersinga WM. Adult hypothyroidism. Thyroid Disease Manager website. http://www.thyroidmanager.org/chapter/adult-hypothyroidism/. Updated March 28, 2014.

(8.) DeGroot LJ. Graves' disease and the manifestations of thyrotoxicosis. Thyroid Disease Manager website. http://www.thyroidmanager.org/chapter/graves-disease-and-the-manifestations-of-thyrotoxicosis/. Updated July 11, 2015.

(9.) Farwell AP. Thyroid hormone therapy is not indicated in the majority of patients with the sick euthyroid syndrome. Endocr Pract. 2008;14(9): 1180-1187.

(10.) Franklin J, Shephard M. Evaluation of thyroid function in health and disease. Thyroid Disease Manager website. http://www.thyroidmanager.org/chapter/evaluation-of-thyroid-function-in-health-and-disease/. Updated September 21, 2000.

(11.) Ergun-Longmire B, Maclaren NK. Etiology and pathogenesis of diabetes mellitus in children. Endotext website. http://www.endotext.org/chapter/diabetes-mellitus/. Updated December 9, 2013.

(12.) Rossi E. Hepcidin--the iron regulatory hormone. Clin Biochem Rev. 2005;26(3):47-49.

(13.) Lodish H, Berk A, Zipursky SL, al. e. Neurotransmitters, synapses, and impulse transmission. Molecular Cell Biology. New York, NY: WH Freeman; 2000.

(14.) Mincu I, Ionescu-Tirgoviste C. Half-life and hypoglycemic effect of intravenous insulin in patients with diabetic ketoacidosis. Med Interne. 1980;18(3):287-292.

(15.) Vasopressin injection, USP [prescribing information]. Schaumburg, IL: APP Pharmaceuticals LLC; 2010.

(16.) Ben-Rafael Z, Levy T, Schoemaker J. Pharmacokinetics of follicle-stimulating hormone: clinical significance. Fertil Steril. 1995;63(4): 689-700.

(17.) Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87(6): 706-727.

(18.) Ross DS, Cooper DS, Mulder JE. Radioiodine in the treatment of hyperthyroidism. UpToDate webste. https://www.uptodate.com/contents/radioiodine-in-the-treatment-of-hyperthyroidism. Updated January 27, 2017.

(19.) Humalog[R] (insulin lispro injection), _for subcutaneous or intravenous use [prescribing information]. Indianapolis, IN: Eli Lilly & Co Inc; 2015.

(20.) Follistim[R] AQ Cartridge (follitropin beta injection) for subcutaneous use Whitehouse Station, NJ: Merck & Co Inc; 2014.

(21.) Desmopressin Acetate Tablets. Sellersville, PA: TEVA Pharmaceuticals; 2007.

(22.) Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9(1):1-25.

(23.) Prednisone Tablets [prescribing information]. Corona, CA: Aidarex Pharmaceuticals LLC; 2017.

(24.) Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335(16):1206-1212.

Laurie Endicott Thomas, MA, ELS /Author and freelance medical writer; Madison, NJ

Laurie Endicott Thomas is the author of Thin Diabetes, Fat Diabetes: Prevent Type 1, Cure Type 2. www.thindiabetes.com

GLOSSARY

adrenal glands--a pair of glands, each of which is found on top of one of the kidneys. The adrenals produce several different hormones

axis--a combined system of neuroendocrine units that regulate the output of an endocrine gland (eg, hypothalamic-pituitary-thyroid axis)

corticosteroids (also called corticoids)--any of the steroid hormones produced by the adrenal cortex, or their synthetic equivalents

endocrine gland--a gland that secretes its product directly into the bloodstream, not through a duct

exocrine gland--a gland that secretes its product through a duct

feedback--the transmission of evaluative or corrective information about an action, event, or process to the original or controlling source

glucocorticoids--any corticoid that increases gluconeogenesis, thus raising blood glucose

hormone--a chemical messenger that is secreted by one tissue (an endocrine gland) but has effects on target tissue in a different organ

neurotransmission--a process in which a cell, upon excitation, releases a specific chemical agent (neuro-transmitter) to cross a gap (synapse) to stimulate or inhibit the cell on the other side of the gap (postsynaptic cell)

peptide--a compound made of typically fewer than 50-100 amino acids

steroid--any of a group of lipids with a complex molecule containing carbon atoms in 4 interlocking rings forming a hydrogenated cyclopentophenanthrene-ring system; 3 of the rings each contain 6 carbon atoms and the fourth ring contains 4 carbon atoms
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Title Annotation:FEATURE SCIENCE SERIES
Author:Thomas, Laurie Endicott
Publication:American Medical Writers Association Journal
Article Type:Report
Date:Jun 22, 2017
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