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The endocrine system produces hormones that function to control and regulate many different body processes. The endocrine system coordinates with the nervous system to control the functions of the other organ systems. Cells of the endocrine system produce molecular signals called hormones. These cells may compose endocrine glands, may be tissues or may be located in organs or tissues that have functions in addition to hormone production. Hormones circulate throughout the body and stimulate a response in cells that have receptors able to bind with them. The changes brought about in the receiving cells affect the functioning of the organ system to which they belong. Many of the hormones are secreted in response to signals from the nervous system, thus the two systems act in concert to effect changes in the body.
Maintaining homeostasis within the body requires the coordination of many different systems and organs. One mechanism of communication between neighboring cells, and between cells and tissues in distant parts of the body, occurs through the release of chemicals called hormones. Hormones are released into body fluids, usually blood, which carries them to their target cells where they elicit a response. The cells that secrete hormones are often located in specific organs, called endocrine glands, and the cells, tissues, and organs that secrete hormones make up the endocrine system. Examples of endocrine organs include the pancreas, which produces the hormones insulin and glucagon to regulate blood-glucose levels, the adrenal glands, which produce hormones such as epinephrine and norepinephrine that regulate responses to stress, and the thyroid gland, which produces thyroid hormones that regulate metabolic rates.
The endocrine glands differ from the exocrine glands. Exocrine glands secrete chemicals through ducts that lead outside the gland (not to the blood). For example, sweat produced by sweat glands is released into ducts that carry sweat to the surface of the skin. The pancreas has both endocrine and exocrine functions because besides releasing hormones into the blood. It also produces digestive juices, which are carried by ducts into the small intestine.
CAREER IN ACTION: Endocrinologist
An endocrinologist is a medical doctor who specializes in treating endocrine disorders. An endocrine surgeon specializes in the surgical treatment of endocrine diseases and glands. Some of the diseases that are managed by endocrinologists include disorders of the pancreas (diabetes mellitus), disorders of the pituitary (gigantism, acromegaly, and pituitary dwarfism), disorders of the thyroid gland (goiter and Graves’ disease), and disorders of the adrenal glands (Cushing’s disease and Addison’s disease).
Endocrinologists are required to assess patients and diagnose endocrine disorders through extensive use of laboratory tests. Many endocrine diseases are diagnosed using tests that stimulate or suppress endocrine organ functioning. Blood samples are then drawn to determine the effect of stimulating or suppressing an endocrine organ on the production of hormones. For example, to diagnose diabetes mellitus, patients are required to fast for 12 to 24 hours. They are then given a sugary drink, which stimulates the pancreas to produce insulin to decrease blood-glucose levels. A blood sample is taken one to two hours after the sugar drink is consumed. If the pancreas is functioning properly, the blood-glucose level will be within a normal range. Another example is the A1C test, which can be performed during blood screening. The A1C test measures average blood-glucose levels over the past two to three months. The A1C test is an indicator of how well blood glucose is being managed over a long time.
Once a disease such as diabetes has been diagnosed, endocrinologists can prescribe lifestyle changes and medications to treat the disease. Some cases of diabetes mellitus can be managed by exercise, weight loss, and a healthy diet; in other cases, medications may be required to enhance insulin’s production or effect. If the disease cannot be controlled by these means, the endocrinologist may prescribe insulin injections.
In addition to clinical practice, endocrinologists may also be involved in primary research and development activities. For example, ongoing islet transplant research is investigating how healthy pancreas islet cells may be transplanted into diabetic patients. Successful islet transplants may allow patients to stop taking insulin injections.
How Hormones Work
Hormones cause changes in target cells by binding to specific cell-surface or intracellularhormone receptors, molecules embedded in the cell membrane or floating in the cytoplasm with a binding site that matches a binding site on the hormone molecule. In this way, even though hormones circulate throughout the body and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Receptors for a specific hormone may be found on or in many different cells or may be limited to a small number of specialized cells. For example, thyroid hormones act on many different tissue types, stimulating metabolic activity throughout the body. Cells can have many receptors for the same hormone but often also possess receptors for different types of hormones. The number of receptors that respond to a hormone determines the cell’s sensitivity to that hormone, and the resulting cellular response. Additionally, the number of receptors available to respond to a hormone can change over time, resulting in increased or decreased cell sensitivity. In up-regulation, the number of receptors increases in response to rising hormone levels, making the cell more sensitive to the hormone and allowing for more cellular activity. When the number of receptors decreases in response to rising hormone levels, called down-regulation, cellular activity is reduced.
The endocrine glands secrete hormones into the surrounding interstitial fluid; those hormones then diffuse into blood and are carried to various organs and tissues within the body. The endocrine glands include the pituitary, thyroid, parathyroid, adrenal glands, gonads, pineal, and pancreas.
The pituitary gland, sometimes called the hypophysis, is located at the base of the brain (Figure 16.4.1a). It is attached to the hypothalamus. The posterior lobe stores and releases oxytocin and antidiuretic hormone produced by the hypothalamus. The anterior lobe responds to hormones produced by the hypothalamus by producing its own hormones, most of which regulate other hormone-producing glands.
The anterior pituitary produces six hormones: growth hormone, prolactin, thyroid-stimulating hormone, adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone. Growth hormone stimulates cellular activities like protein synthesis that promote growth. Prolactin stimulates the production of milk by the mammary glands. The other hormones produced by the anterior pituitary regulate the production of hormones by other endocrine tissues (Table 16.4.1). The posterior pituitary is significantly different in structure from the anterior pituitary. It is a part of the brain, extending down from the hypothalamus, and contains mostly nerve fibers that extend from the hypothalamus to the posterior pituitary.
The thyroid gland is located in the neck, just below the larynx and in front of the trachea (Figure 16.4.1b). It is a butterfly-shaped gland with two lobes that are connected. The thyroid follicle cells synthesize the hormone thyroxine, which is also known as T4 because it contains four atoms of iodine, and triiodothyronine, also known as T3 because it contains three atoms of iodine. T3 and T4 are released by the thyroid in response to thyroid-stimulating hormone produced by the anterior pituitary, and both T3 and T4 have the effect of stimulating metabolic activity in the body and increasing energy use. A third hormone, calcitonin, is also produced by the thyroid. Calcitonin is released in response to rising calcium ion concentrations in the blood and has the effect of reducing those levels.
Most people have four parathyroid glands; however, the number can vary from two to six. These glands are located on the posterior surface of the thyroid gland (Figure 16.4.1b).
The parathyroid glands produce parathyroid hormone. Parathyroid hormone increases blood calcium concentrations when calcium ion levels fall below normal.
The adrenal glands are located on top of each kidney (Figure 16.4.1c). The adrenal glands consist of an outer adrenal cortex and an inner adrenal medulla. These regions secrete different hormones.
The adrenal cortex produces mineralocorticoids, glucocorticoids, and androgens. The main mineralocorticoid is aldosterone, which regulates the concentration of ions in urine, sweat, and saliva. Aldosterone release from the adrenal cortex is stimulated by a decrease in blood concentrations of sodium ions, blood volume, or blood pressure, or by an increase in blood potassium levels. The glucocorticoids maintain proper blood-glucose levels between meals. They also control a response to stress by increasing glucose synthesis from fats and proteins and interact with epinephrine to cause vasoconstriction. Androgens are sex hormones that are produced in small amounts by the adrenal cortex. They do not normally affect sexual characteristics and may supplement sex hormones released from the gonads. The adrenal medulla contains two types of secretory cells: one that produces epinephrine (adrenaline) and another that produces norepinephrine (noradrenaline). Epinephrine and norepinephrine cause immediate, short-term changes in response to stressors, inducing the so-called fight-or-flight response. The responses include increased heart rate, breathing rate, cardiac muscle contractions, and blood-glucose levels. They also accelerate the breakdown of glucose in skeletal muscles and stored fats in adipose tissue, and redirect blood flow toward skeletal muscles and away from skin and viscera. The release of epinephrine and norepinephrine is stimulated by neural impulses from the sympathetic nervous system that originate from the hypothalamus.
The pancreas is an elongate organ located between the stomach and the proximal portion of the small intestine (Figure 16.4.1d). It contains both exocrine cells that excrete digestive enzymes and endocrine cells that release hormones.
The endocrine cells of the pancreas form clusters called pancreatic islets or the islets of Langerhans. Among the cell types in each pancreatic islet are the alpha cells, which produce the hormone glucagon, and the beta cells, which produce the hormone insulin. These hormones regulate blood-glucose levels. Alpha cells release glucagon as blood-glucose levels decline. When blood-glucose levels rise, beta cells release insulin. Glucagon causes the release of glucose to the blood from the liver, and insulin facilitates the uptake of glucose by the body’s cells.
The gonads—the male testes and female ovaries—produce steroid hormones. The testes produce androgens, testosterone being the most prominent, which allow for the development of secondary sex characteristics and the production of sperm cells. The ovaries produce estrogen and progesterone, which cause secondary sex characteristics, regulate production of eggs, control pregnancy, and prepare the body for childbirth.
There are several organs whose primary functions are non-endocrine but that also possess endocrine functions. These include the heart, kidneys, intestines, thymus, and adipose tissue. The heart has endocrine cells in the walls of the atria that release a hormone in response to increased blood volume. It causes a reduction in blood volume and blood pressure, and reduces the concentration of Na+ in the blood.
The gastrointestinal tract produces several hormones that aid in digestion. The endocrine cells are located in the mucosa of the GI tract throughout the stomach and small intestine. They trigger the release of gastric juices, which help to break down and digest food in the GI tract.
The kidneys also possess endocrine function. Two of these hormones regulate ion concentrations and blood volume or pressure. Erythropoietin (EPO) is released by kidneys in response to low oxygen levels. EPO triggers the formation of red blood cells in the bone marrow. EPO has been used by athletes to improve performance. But EPO doping has its risks, since it thickens the blood and increases strain on the heart; it also increases the risk of blood clots and therefore heart attacks and stroke.
The thymus is found behind the sternum. The thymus produces hormones referred to as thymosins, which contribute to the development of the immune response in infants. Adipose tissue, or fat tissue, produces the hormone leptin in response to food intake. Leptin produces a feeling of satiety after eating, reducing the urge for further eating.
|Table 16.4.1: Endocrine Glands and Their Associated Hormones|
|Endocrine Gland||Associated Hormones||Effect|
|Pituitary (anterior)||growth hormone||promotes growth of body tissues|
|prolactin||promotes milk production|
|thyroid-stimulating hormone||stimulates thyroid hormone release|
|adrenocorticotropic hormone||stimulates hormone release by adrenal cortex|
|follicle-stimulating hormone||stimulates gamete production|
|luteinizing hormone||stimulates androgen production by gonads in males; stimulates ovulation and production of estrogen and progesterone in females|
|Pituitary (posterior)||antidiuretic hormone||stimulates water reabsorption by kidneys|
|oxytocin||stimulates uterine contractions during childbirth|
|Thyroid||thyroxine, triiodothyronine||stimulate metabolism|
|calcitonin||reduces blood Ca2+ levels|
|Parathyroid||parathyroid hormone||increases blood Ca2+ levels|
|Adrenal (cortex)||aldosterone||increases blood Na+ levels|
|cortisol, corticosterone, cortisone||increase blood-glucose levels|
|Adrenal (medulla)||epinephrine, norepinephrine||stimulate fight-or-flight response|
|Pancreas||insulin||reduces blood-glucose levels|
|glucagon||increases blood-glucose levels|
Regulation of Hormone Production
Hormone production and release are primarily controlled by negative feedback, as described in the discussion on homeostasis. In this way, the concentration of hormones in blood is maintained within a narrow range. For example, the anterior pituitary signals the thyroid to release thyroid hormones. Increasing levels of these hormones in the blood then give feedback to the hypothalamus and anterior pituitary to inhibit further signaling to the thyroid gland (Figure 16.4.2).
Goiter, a disease caused by iodine deficiency, results in the inability of the thyroid gland to form T3 and T4. The body typically attempts to compensate by producing greater amounts of TSH. Which of the following symptoms would you expect goiter to cause?
- Hypothyroidism, resulting in weight gain, cold sensitivity, and reduced mental activity.
- Hyperthyroidism, resulting in weight loss, profuse sweating, and increased heart rate.
- Hyperthyroidism, resulting in weight gain, cold sensitivity, and reduced mental activity.
- Hypothyroidism, resulting in weight loss, profuse sweating, and increased heart rate.
Hormones cause cellular changes by binding to receptors on or in target cells. The number of receptors on a target cell can increase or decrease in response to hormone activity.
Hormone levels are primarily controlled through negative feedback, in which rising levels of a hormone inhibit its further release.
The pituitary gland is located at the base of the brain. The anterior pituitary receives signals from the hypothalamus and produces six hormones. The posterior pituitary is an extension of the brain and releases hormones (antidiuretic hormone and oxytocin) produced by the hypothalamus. The thyroid gland is located in the neck and is composed of two lobes. The thyroid produces the hormones thyroxine and triiodothyronine. The thyroid also produces calcitonin. The parathyroid glands lie on the posterior surface of the thyroid gland and produce parathyroid hormone.
The adrenal glands are located on top of the kidneys and consist of the adrenal cortex and adrenal medulla. The adrenal cortex produces the corticosteroids, glucocorticoids and mineralocorticoids. The adrenal medulla is the inner part of the adrenal gland and produces epinephrine and norepinephrine.
The pancreas lies in the abdomen between the stomach and the small intestine. Clusters of endocrine cells in the pancreas form the islets of Langerhans, which contain alpha cells that release glucagon and beta cells that release insulin. Some organs possess endocrine activity as a secondary function but have another primary function. The heart produces the hormone atrial natriuretic peptide, which functions to reduce blood volume, pressure, and Na+concentration. The gastrointestinal tract produces various hormones that aid in digestion. The kidneys produce erythropoietin. The thymus produces hormones that aid in the development of the immune system. The gonads produce steroid hormones, including testosterone in males and estrogen and progesterone in females. Adipose tissue produces leptin, which promotes satiety signals in the brain.
Figure 16.4.2 Goiter, a disease caused by iodine deficiency, results in the inability of the thyroid gland to form T3 and T4. Which of the following symptoms would you expect goiter to cause?
A. Hypothyroidism, resulting in weight gain, cold sensitivity, and reduced mental activity.
B. Hyperthyroidism, resulting in weight loss, profuse sweating and increased heart rate.
C. Hyperthyroidism, resulting in weight gain, cold sensitivity, and reduced mental activity.
D. Hypothyroidism, resulting in weight loss, profuse sweating and increased heart rate.
Figure 16.4.2 A
Most of the hormones produced by the anterior pituitary perform what function?
A. regulate growth
B. regulate the sleep cycle
C. regulate production of other hormones
D. regulate blood volume and blood pressure
What is the function of the hormone erythropoietin?
A. stimulates production of red blood cells
B. stimulates muscle growth
C. causes the fight-or-flight response
D. causes testosterone production
Which endocrine glands are associated with the kidneys?
A. thyroid glands
B. pituitary glands
C. adrenal glands
What is a similarity and a difference between an exocrine gland and an endocrine gland?
The cells of both exocrine and endocrine glands produce a product that will be secreted by the gland. An exocrine gland has a duct and secretes its product to the outside of the gland, not into the bloodstream. An endocrine gland secretes its product into the bloodstream and does not use a duct.
Describe how hormone receptors can play a role in affecting the size of the responses of tissues to hormones.
The number of receptors that respond to a hormone can change, resulting in increased or decreased cell sensitivity. The number of receptors can increase in response to rising hormone levels, called up-regulation, making the cell more sensitive to the hormone and allowing for more cellular activity. The number of receptors can also decrease in response to rising hormone levels, called down-regulation, leading to reduced cellular activity.
Many hormone systems regulate body functions through opposing hormone actions. Describe how opposing hormone actions regulate blood-glucose levels?
Blood-glucose levels are regulated by hormones produced by the pancreas: insulin and glucagon. When blood-glucose levels are increasing, the pancreas releases insulin, which stimulates uptake of glucose by cells. When blood-glucose levels are decreasing, the pancreas releases glucagon, which stimulates the release of stored glucose by the liver to the bloodstream.
- adrenal gland
- the endocrine gland associated with the kidneys
- a decrease in the number of hormone receptors in response to increased hormone levels
- endocrine gland
- the gland that secretes hormones into the surrounding interstitial fluid, which then diffuse into blood and are carried to various organs and tissues within the body
- exocrine gland
- the gland that secretes chemicals through ducts that lead to skin surfaces, body cavities, and organ cavities.
- a chemical released by cells in one area of the body that affects cells in other parts of the body
- intracellular hormone receptor
- a hormone receptor in the cytoplasm or nucleus of a cell
- the organ located between the stomach and the small intestine that contains exocrine and endocrine cells
- parathyroid gland
- the gland located on the surface of the thyroid that produces parathyroid hormone
- pituitary gland
- the endocrine gland located at the base of the brain composed of an anterior and posterior region; also called hypophysis
- the gland located behind the sternum that produces thymosin hormones that contribute to the development of the immune system
- thyroid gland
- an endocrine gland located in the neck that produces thyroid hormones thyroxine and triiodothyronine
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Environmental endocrine disruptors: Effects on the human male reproductive system
Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.
Keywords: Carcinogenesis Developmental origins of adult disease Endocrine disruption Male breast cancer Male reproduction Prostate cancer Testicular cancer Tissue organization field theory.
Conflict of interest statement
Conflict of Interest: The authors declare that they have no conflict of interest.
28.2 Hypothalamic–pituitary–thyroid axis
The hypothalamic–pituitary–thyroid axis (HPT axis for short, a.k.a. thyroid homeostasis or thyrotropic feedback control) is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.
As its name suggests, it depends upon the hypothalamus, the pituitary gland, and the thyroid gland.
The hypothalamus senses low circulating levels of thyroid hormone (Triiodothyronine (T3) and Thyroxine (T4)) and responds by releasing thyrotropin-releasing hormone (TRH). The TRH stimulates the anterior pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone until levels in the blood return to normal. Thyroid hormone exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland.
Thyroid homeostasis results from a multi-loop feedback system that is found in virtually all higher vertebrates. Proper function of thyrotropic feedback control is indispensable for growth, differentiation, reproduction and intelligence. Very few animals (e.g. axolotls and sloths) have impaired thyroid homeostasis that exhibits a very low set-point that is assumed to underlie the metabolic and ontogenetic anomalies of these animals.
The pituitary gland secretes thyrotropin (TSH Thyroid Stimulating Hormone) that stimulates the thyroid to secrete thyroxine (T4) and, to a lesser degree, triiodothyronine (T3). The major portion of T3, however, is produced in peripheral organs, e.g. liver, adipose tissue, glia and skeletal muscle by deiodination from circulating T4. Deiodination is controlled by numerous hormones and nerval signals including TSH, vasopressin and catecholamines.
Both peripheral thyroid hormones (iodothyronines) inhibit thyrotropin secretion from the pituitary (negative feedback). Consequently, equilibrium concentrations for all hormones are attained.
TSH secretion is also controlled by thyrotropin releasing hormone (thyroliberin, TRH), whose secretion itself is again suppressed by plasma T4 and T3 in CSF (long feedback, Fekete–Lechan loop). Additional feedback loops are ultrashort feedback control of TSH secretion (Brokken-Wiersinga-Prummel loop) and linear feedback loops controlling plasma protein binding.
Recent research suggested the existence of an additional feedforward motif linking TSH release to deiodinase activity in humans. The existence of this TSH-T3 shunt could explain why deiodinase activity is higher in hypothyroid patients and why a minor fraction of affected individuals may benefit from substitution therapy with T3.
Convergence of multiple afferent signals in the control of TSH release including but not limited to T3, cytokines and TSH receptor antibodies may be the reason for the observation that the relation between free T4 concentration and TSH levels deviates from a pure loglinear relation that has previously been proposed.
Many chemicals, both natural and man-made, may mimic or interfere with the body&rsquos hormones, known as the endocrine system. Called endocrine disruptors, these chemicals are linked with developmental, reproductive, brain, immune, and other problems.
Endocrine disruptors are found in many everyday products, including some plastic bottles and containers, liners of metal food cans, detergents, flame retardants, food, toys, cosmetics, and pesticides.
Some endocrine-disrupting chemicals are slow to break-down in the environment. That characteristic makes them potentially hazardous over time.
Endocrine disrupting chemicals cause adverse effects in animals. But limited scientific information exists on potential health problems in humans. Because people are typically exposed to multiple endocrine disruptors at the same time, assessing public health effects is difficult.
What are some common endocrine disruptors?
- Bisphenol A (BPA) &mdash used to make polycarbonate plastics and epoxy resins, which are found in many plastic products including food storage containers
- Dioxins &mdash produced as a byproduct in herbicide production and paper bleaching, they are also released into the environment during waste burning and wildfires
- Perchlorate &mdash a by-product of aerospace, weapon, and pharmaceutical industries found in drinking water and fireworks
- Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) &mdash used widely in industrial applications, such as firefighting foams and non-stick pan, paper, and textile coatings
- Phthalates &mdash used to make plastics more flexible, they are also found in some food packaging, cosmetics, children&rsquos toys, and medical devices
- Phytoestrogens &mdash naturally occurring substances in plants that have hormone-like activity, such as genistein and daidzein that are in soy products, like tofu or soy milk
- Polybrominated diphenyl ethers (PBDE) &mdash used to make flame retardants for household products such as furniture foam and carpets
- Polychlorinated biphenyls (PCB) &mdash used to make electrical equipment like transformers, and in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers
- Triclosan &mdash may be found in some anti-microbial and personal care products, like liquid body wash
How do people encounter endocrine-disrupting chemicals?
People may be exposed to endocrine disruptors through food and beverages consumed, pesticides applied, and cosmetics used. In essence, your contact with these chemicals may occur through diet, air, skin, and water.
Even low doses of endocrine-disrupting chemicals may be unsafe. The body&rsquos normal endocrine functioning involves very small changes in hormone levels, yet we know even these small changes can cause significant developmental and biological effects. This observation leads scientists to think that endocrine-disrupting chemical exposures, even at low amounts, can alter the body&rsquos sensitive systems and lead to health problems.
Endocrine Disruptors and Your Health
What is NIEHS Doing?
For more than three decades, NIEHS has been a pioneer in conducting research on the health effects of endocrine disruptors. NIEHS-supported research leads to a greater understanding of how endocrine-disrupting chemicals may harm our health and cause disease.
This work began with studies on the endocrine-disrupting effects of the drug diethylstilbestrol (DES). From 1940s through 1970s, DES was used to treat women with high-risk pregnancies, with the mistaken belief that it prevented miscarriage. In 1972, prenatal exposure to DES was linked to the development of a rare form of vaginal cancer in daughters whose mothers took DES, and with numerous noncancerous changes in both sons and daughters. NIEHS experiments on DES successfully replicated and predicted health problems, which was useful in discovering how DES may harm wellbeing.
NIEHS was involved in developing a consensus statement in 2019 on the key characteristics of endocrine-disrupting chemicals , which provides a framework to help scientists evaluate potential endocrine disruptors.
NIEHS leads cutting-edge research projects on endocrine disrupting chemicals to understand how they work and define their role in health and disease. Research areas in progress include:
- Developing new models and tools to better understand how endocrine disrupters work
- Developing and applying high throughout assays to identify substances with endocrine disrupting activity
- Conducting animal and human health research to define linkages between exposure to endocrine disrupters and health effects
- Developing new assessments and biomarkers of exposure and toxicity
- Identifying and developing new intervention and prevention strategies
Related work of the National Toxicology Program
In 2000, an independent panel of experts convened by NIEHS and the National Toxicology Program (NTP) , which is housed at NIEHS, concluded there was credible evidence that very low doses of some hormone-like chemicals can adversely affect bodily functions in test animals.
NTP is evaluating endocrine disrupters including pesticides, perfluorinated chemicals, compounds that may replace BPA in the marketplace, and components of flame-retardants for how they may affect body tissues such as breast, uterus, fat cells, male reproductive tract, and liver. In addition, they conduct laboratory studies that help them prioritize endocrine disrupting chemicals for further toxicity testing.
NTP scientists collaborate with researchers from the U.S. Environmental Protection Agency (EPA) to develop and validate integrated, high throughput testing strategies to detect substances that could disrupt endocrine functions by interacting with the hormones estrogen and androgen. In addition, they created a comprehensive database from thousands of scientific studies on how different substances interact with hormones.
The multi-agency Tox 21 program, in which NIEHS participates, is developing and applying new models and tools using robotics to predict endocrine disrupting activity for environmental substances.
What has NIEHS discovered?
NIEHS-supported research has discovered links between endocrine-disrupting chemicals and the ways in which wellbeing may be harmed, as shown by the following examples:
16.4: Endocrine System - Biology
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The endocrine system consists of cells, tissues, glands, and organs that produce, secrete, and regulate hormones, chemical signals that communicate between neighboring cells and more distant sites within the body.
Different hormones can be secreted into the extracellular fluid and move through the circulatory system to many cell types. But they only affect certain targets, such as cells with specialized receptors for a particular hormone.
In this way, the endocrine system maintains a number of biological processes, including homeostasis, metabolism, and reproduction and development.
21.1: What is the Endocrine System?
The endocrine system sends hormones&mdashchemical signals&mdashthrough the bloodstream to target cells&mdashthe cells the hormones selectively affect. These signals are produced in endocrine cells, secreted into the extracellular fluid, and then diffuse into the blood. Eventually, they diffuse out of the blood and bind to target cells which have specialized receptors to recognize the hormones.
While most hormones travel through the circulatory system to reach their target cells, there are also alternate routes to bring hormones to target cells. Paracrine signaling sends hormones out of the endocrine cell and into the extracellular fluid where they affect local cells. In a form of paracrine signaling, called autocrine signaling, hormones secreted into the extracellular fluid affect the cell that secreted them.
Another type of signaling, synaptic signaling, involves the release of neurotransmitters from neuron terminals into the synapse&mdasha specialized junction that relays information between neurons&mdashwhere they bind to receptors on neighboring neurons, muscle cells, and glands. In neuroendocrine signaling, neurosecretory cells secrete neurohormones that travel through the blood to affect target cells. Overall, endocrine signaling has a slower effect than other types of signaling because it takes longer for hormones to reach the target cells, but the effects typically also last longer.
Hormones directly diffuse into the extracellular fluid surrounding the endocrine glands because they have no ducts. In comparison, exocrine glands, like the salivary gland, have ducts that secrete a targeted dose directly onto a surface or into a cavity. In addition to being found in specialized endocrine glands, endocrine cells can also be located in organs like the stomach, among cells with different functions.
A hormone has specific target cells that have receptors that recognize the hormone. It can be thought of like a lock and key where the receptors on a target cell are the lock and will only recognize the hormone, the key, that fits it. Target cells can be very close to the endocrine cells that produce the hormone or very far away but must be transported through the bloodstream. For instance, enteroendocrine cells in the stomach and small intestine release hormones that can alter gastric acid secretion by stomach cells. On the other hand, hormones released by the pituitary gland located at the base of the brain can affect urine production by acting on kidney cells.
Jones, Christopher M., and Kristien Boelaert. &ldquoThe Endocrinology of Ageing: A Mini-Review.&rdquo Gerontology 61, no. 4 (2015): 291&ndash300. [Source]
Yang, Oneyeol, Hye Lim Kim, Jong-Il Weon, and Young Rok Seo. &ldquoEndocrine-Disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis.&rdquo Journal of Cancer Prevention 20, no. 1 (March 2015): 12&ndash24. [Source]
Non-exercise activity thermogenesis (NEAT)
Non-exercise activity thermogenesis (NEAT) is the energy expended for everything we do that is not sleeping, eating or sports-like exercise. It ranges from the energy expended walking to work, typing, performing yard work, undertaking agricultural tasks and fidgeting. Even trivial physical activities increase metabolic rate substantially and it is the cumulative impact of a multitude of exothermic actions that culminate in an individual's daily NEAT. It is, therefore, not surprising that NEAT explains a vast majority of an individual's non-resting energy needs. Epidemiological studies highlight the importance of culture in promoting and quashing NEAT. Agricultural and manual workers have high NEAT, whereas wealth and industrialization appear to decrease NEAT. Physiological studies demonstrate, intriguingly, that NEAT is modulated with changes in energy balance NEAT increases with overfeeding and decreases with underfeeding. Thus, NEAT could be a critical component in how we maintain our body weight and/or develop obesity or lose weight. The mechanism that regulates NEAT is unknown. However, hypothalamic factors have been identified that specifically and directly increase NEAT in animals. By understanding how NEAT is regulated we may come to appreciate that spontaneous physical activity is not spontaneous at all but carefully programmed.
Electrical control of behaviour: The nervous system
The nervous system (see Figure 3.13), which is the electrical information highway of the body, is made up of nerves, which are bundles of interconnected neurons that fire in synchrony to carry messages. Made up of the brain and spinal cord, the central nervous system (CNS) is the major controller of the body’s functions it is tasked with interpreting sensory information and responding to it with its own directives. The CNS interprets information coming in from the senses, formulates an appropriate reaction, and sends responses to the appropriate system to respond accordingly. Everything that we see, hear, smell, touch, and taste is conveyed to us from our sensory organs as neural impulses, and each of the commands that the brain sends to the body, both consciously and unconsciously, travels through this system as well.
Figure 3.13. The nervous system is made up of the central nervous system and the peripheral nervous system. [Long description]
Nerves are differentiated according to their function. A sensory (or afferent) neuron carries information from the sensory receptors, whereas a motor (or efferent) neuron transmits information to the muscles and glands. An interneuron, which is by far the most common type of neuron, is located primarily within the CNS and is responsible for communicating among the neurons. Interneurons allow the brain to combine the multiple sources of available information to create a coherent picture of the sensory information being conveyed.
The spinal cord is the long, thin, tubular bundle of nerves and supporting cells that extends down from the brain. It is the central pathway of information for the body. Within the spinal cord, ascending tracts of sensory neurons relay sensory information from the sense organs to the brain while descending tracts of motor neurons relay motor commands back to the body. When a quicker-than-usual response is required, the spinal cord can do its own processing, bypassing the brain altogether. A reflex is an involuntary and nearly instantaneous movement in response to a stimulus. Reflexes are triggered when sensory information is powerful enough to reach a given threshold and the interneurons in the spinal cord act to send a message back through the motor neurons without relaying the information to the brain (see Figure 3.14). When you touch a hot stove and immediately pull your hand back or when you mishandle your cell phone and instinctively reach to catch it before it falls, reflexes in your spinal cord order the appropriate responses before your brain even knows what is happening.
Figure 3.14. The central nervous system can interpret signals from sensory neurons and respond to them extremely quickly via the motor neurons without any need for the brain to be involved. These quick responses, known as reflexes, can reduce the damage that we might experience as a result of, for instance, touching a hot stove.
If the central nervous system is the command centre of the body, the peripheral nervous system represents the front line. The peripheral nervous system (PNS) links the CNS to the body’s sense receptors, muscles, and glands. The peripheral nervous system is itself divided into two subsystems, one controlling external responses and one controlling internal responses.
The somatic nervous system (SNS) is the division of the PNS that controls the external aspects of the body, including the skeletal muscles, skin, and sense organs. The somatic nervous system consists primarily of motor nerves responsible for sending brain signals for muscle contraction.
The autonomic nervous system (ANS) is the division of the PNS that governs the internal activities of the human body, including heart rate, breathing, digestion, salivation, perspiration, urination, and sexual arousal. Many of the actions of the ANS, such as heart rate and digestion, are automatic and out of our conscious control, but others, such as breathing and sexual activity, can be controlled and influenced by conscious processes.
The autonomic nervous system itself can be further subdivided into the sympathetic and parasympathetic systems (see Figure 3.15). The sympathetic division of the ANS is involved in preparing the body for behaviour, particularly in response to stress, by activating the organs and the glands in the endocrine system. The parasympathetic division of the ANS tends to calm the body by slowing the heart and breathing and by allowing the body to recover from the activities that the sympathetic system causes. The sympathetic and the parasympathetic divisions normally function in opposition to each other, with the sympathetic division acting a bit like the accelerator of a vehicle and the parasympathetic division acting like the brake.
Figure 3.15. The autonomic nervous system is divided into the sympathetic division, which acts to energize the body and prepares it for action, and the parasympathetic division, which acts to calm the body and allows it to rest. [Long description]
Our everyday activities are controlled by the interaction between the sympathetic and parasympathetic nervous systems. For example, when we get out of bed in the morning, we would experience a sharp drop in blood pressure if it were not for the action of the sympathetic system, which automatically increases blood flow through the body. Similarly, after we eat a big meal, the parasympathetic system automatically sends more blood to the stomach and intestines, allowing us to efficiently digest the food. Perhaps you have had the experience of not being hungry at all before a stressful event, such as a sports game or an exam when the sympathetic division was primarily in action, but suddenly found yourself feeling starved afterward as the parasympathetic takes over. The two systems work together to maintain vital bodily functions, resulting in homeostasis, which is the natural balance in the body’s systems.
The main endocrine glands include :
- Pituitary gland, pineal gland and hypothalamus – head
- Thyroid gland and parathyroid glands – neck and upper chest
- Pancreas and adrenal glands (on top of kidney) – upper abdomen
- Ovaries (female) and testes (male) – pelvis and perineum
Other sites in the body including organs like the stomach and tissue like adipose tissue can also produce and secrete hormones but are not considered as endocrine glands. In certain disease states, like in cancer, the tumor may secrete hormones into the blood stream – carcinoid syndrome.
16.4: Endocrine System - Biology
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Endocrine signaling occurs when cells located in different organs need to communicate, such as when the pituitary gland communicates with the kidneys. When this happens, hormones, the signaling ligands, use the bloodstream to reach their target cells.
For example, the pituitary gland signals the kidneys to reabsorb water from urine, by releasing the hormone arginine vasopressin, or AVP, into the blood. When blood is filtered in the kidneys, AVP binds to its G protein-coupled receptor, AVPR2, on targeted renal cells.
Upon activation by the hormone, the G protein subunits decouple from the receptor, and activate adenylate cyclase, to make the second messenger, cyclic AMP. Cyclic AMP activates the intracellular signaling cascade involving protein kinase A, or PKA.
PKA has two functions. First, it phosphorylates the aquaporin channel, APQ2, held in reserve in cytoplasmic vesicles. This action brings the vesicle, and the channels, to the cell membrane, allowing the flow of water back into the renal cells.
Secondly, PKA phosphorylates CREB in the nucleus, causing it to bind to the aquaporin 2 gene, and start its transcription and then translation for new aquaporin channels.
Thus, endocrine signaling is a crucial step in osmoregulation, and other functions where remote cell groups must communicate.
6.10: Endocrine Signaling
Endocrine cells produce hormones to communicate with remote target cells found in other organs. The hormone reaches these distant areas using the circulatory system. This exposes the whole organism to the hormone but only those cells expressing hormone receptors or target cells are affected. Thus, endocrine signaling induces slow responses from its target cells but these effects also last longer.
There are two types of endocrine receptors: cell surface receptors and intracellular receptors. Cell surface receptors work similarly to other membrane bound receptors. Hormones, the ligand, bind to a hormone specific G-protein coupled receptor. This initiates conformational changes in the receptor, releasing a subunit of the G-protein. The protein activates second messengers which internalize the message by triggering signaling cascades and transcription factors.
Many hormones work through cell surface receptors, including epinephrine, norepinephrine, insulin, prostaglandins, prolactin, and growth hormones.
Steroid hormones, like testosterone, estrogen, and progesterone, transmit signals using intracellular receptors. These hormones are small hydrophobic molecules so they move directly past the outer cell membrane. Once inside, and if that cell is a target cell, the hormone binds to its receptor. Binding creates a conformational change in the receptor which activates its potential as a transcription factor. Once activated, the receptor or hormone-receptor complex promote or suppress gene expression.
The intracellular hormone receptors are a large superfamily of receptors but they all have a similar single polypeptide chain with three distinct domains. The N-terminus is the active transcription factor domain. The middle contains a DNA binding domain specific for the gene of interest. And the hormone binds to a domain at the C-terminus.
Iliodromiti, Zoe, Nikolaos Antonakopoulos, Stavros Sifakis, Panagiotis Tsikouras, Angelos Daniilidis, Kostantinos Dafopoulos, Dimitrios Botsis, and Nikolaos Vrachnis. &ldquoEndocrine, Paracrine, and Autocrine Placental Mediators in Labor.&rdquo Hormones (Athens, Greece) 11, no. 4 (December 2012): 397&ndash409. [Source]
Mayer, Emeran A., Rob Knight, Sarkis K. Mazmanian, John F. Cryan, and Kirsten Tillisch. &ldquoGut Microbes and the Brain: Paradigm Shift in Neuroscience.&rdquo Journal of Neuroscience 34, no. 46 (November 12, 2014): 15490&ndash96. [Source]
The Endocrine System
The endocrine system is a series of glands that produce and secrete hormones that the body uses for a wide range of functions. These control many different bodily functions, including:
- Sensory perception
- Sexual development
Hormones are produced by glands and sent into the bloodstream to the various tissues in the body. They send signals to those tissues to tell them what they are supposed to do. When the glands do not produce the right amount of hormones, diseases develop that can affect many aspects of life.
The main hormone-producing glands are:
- : The hypothalamus is responsible for body temperature, hunger, moods and the release of hormones from other glands and also controls thirst, sleep and sex drive.
: Considered the "master control gland," the pituitary gland controls other glands and makes the hormones that trigger growth.
: This gland controls the amount of calcium in the body.
: This gland produces the insulin that helps control blood sugar levels.
: The thyroid produces hormones associated with calorie burning and heart rate.
: Adrenal glands produce the hormones that control sex drive and cortisol, the stress hormone.
: This gland produces melatonin which affect sleep.
: Only in women, the ovaries secrete estrogen, testosterone and progesterone, the female sex hormones.
: Only in men, the testes produce the male sex hormone, testosterone, and produce sperm.
Some of the factors that affect endocrine organs include aging, certain diseases and conditions, stress, the environment, and genetics.