Information

Effect of steroid hormone on specific cells?

Effect of steroid hormone on specific cells?


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

As steroid hormones can pass through the plasma membrane by simple diffusion because they are lipid derived hormones, it means that they are capable of passing through every cell of our body, BUT why are only specific cells responsive against steroid hormones?

For example, all of our body cells almost contains the genes for the development of secondary sexual characters but why do only specific cells show a response against these steroid hormones because the development of secondary sexual characters occur only in specific region of our body, that is, beard formation occur only in a specific region of the face, etc.

IN SUMMARY: When steroid hormones can pass through every cell of our body then why do they show only a localized response?


Unlike other types of hormones, steroid hormones do not have to bind to plasma membrane receptors. Instead, they can interact with intracellular receptors that are themselves transcription activators. Steroid hormones too hydrophobic to dissolve readily in the blood travel on specific carrier proteins from their point of release to their target tissues. In the target tissue, the hormone passes through the plasma membrane by simple diffusion and binds to its specific receptor protein in the cytoplasm. The receptor-hormone complex then translocates into the nucleus where it acts by binding to highly specific DNA sequences called hormone response elements (HREs), thereby altering gene expression. Hormone binding triggers changes in the conformation of the receptor proteins so that they be- come capable of interacting with additional transcription factors. The bound hormone-receptor complex can either enhance or suppress the expression of adjacent genes. The DNA sequences (HREs) to which hormone- receptor complexes bind are similar in length and arrangement, but differ in sequence, for the various steroid hormones. Each receptor has a consensus HRE sequence to which the hormone-receptor complex binds well, with each consensus consisting of two six-nucleotide sequences, either contiguous or separated by three nucleotides, The ability of a given hormone to act through the hormone-receptor complex to alter the expression of a specific gene depends on the exact sequence of the HRE, its position relative to the gene, and the number of HREs associated with the gene.


The quick answer is that only certain cell types express the required steroid hormone receptors that are necessary to induce signaling and gene regulation when bound to their target steroid hormones, like estrogen, testosterone, cortisol, etc. If no receptor is present, the steroid doesn't effect any change.

The second part of the answer involves the particular signaling pathways induced by the ligation of certain receptors by certain classes of hormones. Testosterone, for example, has numerous effects across the body, from promoting the growth of hair to building muscle mass to effects on mental well-being. Testosterone and its primary metabolite 5α-dihydrotestosterone bind primarily to the cytoplasmic androgen receptor, which then translocates to the nucleus, binds DNA at hormone response elements, and alters the transcriptional activity of genes (either increasing or decreasing, depending on the gene and the cell type). Testosterone can also be metabolized to estradiol and bind estrogen receptors, which function similarly to the androgen receptor (although it can have DNA-independent effects as well).

So, depending on the cell type, receptor expression levels, other DNA regulatory elements, the presence or absence of various testosterone-metabolizing enzymes, and other factors like age, gender, etc., a single steroid hormone can have a multitude of effects throughout the body.


Endocrine Glands

Steroid hormones

Steroid hormone–secreting endocrine cells are characterized by large lipid vacuoles in the cytoplasm that contain cholesterol esters and other precursor molecules. The lipid vacuoles are in close proximity to an extensive tubular network of smooth endoplasmic reticulum and large mitochondria that contain the hydroxylase and dehydrogenase cytochrome P450 enzyme systems. These enzymes function to attach or modify various side chains to the basic steroid molecule. Steroid-producing cells lack secretory granules and do not store significant amounts of preformed hormone. They are dependent on continued biosynthesis to maintain the normal secretory rate for a particular hormone.

Steroid hormones originating from cholesterol precursor molecules account for

15% of mammalian hormones. They are lipid soluble, which facilitates their transport through the cell membrane. In the cytoplasm, steroid hormones bind to receptors that form homodimers or heterodimers, migrate to the nucleus, and function as nuclear receptors and transcription factors. The steroid hormone receptors have binding sites for the steroid hormone, specific regions of the genomic DNA, and accessory regulatory proteins. After binding to the genomic DNA and accessory proteins, the receptor complexes either upregulate or downregulate gene transcription of multiple genes and direct protein synthesis by the target cells. Recent evidence suggests that nongenomic steroid hormone signaling exists under specific circumstances. The nongenomic cellular responses to steroid hormones are very fast and may involve cell membrane–binding proteins. Steroid hormones have a long half-life in blood (typically measured in hours) and reversibly bind to high-affinity, specific binding proteins for transport in plasma.


Introduction

Follicular development begins during foetal life with the transformation of primordial germ cells into oocytes and their enclosure in structures called follicles. In most mammals, primordial follicles form either before, or in the first few days after birth. Primordial follicles give rise to primary follicles which transform into preantral (secondary follicles) then antral follicles (tertiary follicles) and finally preovulatory, Graafian follicles, in a co-ordinated series of transitions regulated by hormones and local intraovarian factors. The growth and differentiation of follicles from the primordial population is termed folliculogenesis. With the LH surge, Graafian follicles rupture and oocytes are released, leaving the follicular cells to luteinise and form a corpus luteum.

Sex steroids play important roles in the growth and differentiation of reproductive tissues and in the maintenance of fertility. Produced de novo from cholesterol, progestins, androgens and oestrogens are synthesised by the ovary in a sequential manner, with each serving as substrate for the subsequent steroid in the pathway. The two-cell, two-gonadotrophin model describes the role of theca and granulosa cells in the production of steroids, highlighting the cooperation between the two cell types, which is necessary for oestrogen production (Figure 1). Given that signal transduction for these hormones usually requires the binding and activation of a ligand-specific receptor, one cannot easily dissociate these components and assign definitive roles. The steroid hormones signal via nuclear receptors to regulate transcriptional events. These receptors form part of a nuclear receptor superfamily, all of which contain common structural elements [1, 2]. These include a highly conserved DNA binding domain (DBD), a moderately conserved ligand binding domain (LBD) and 2 transactivation domains, AF1 located in domain A/B and AF2 in domain E/F (Figure 2). This review will address the roles that steroid hormones play in follicular development. It will encompass the direct actions of steroids in the ovary that have been reported and include a discussion of relevant models of ovarian dysfunction and nuclear receptor knockout mouse models that lead to disruption of steroid hormone signalling mechanisms and thus an inability of steroids to fulfil their regulatory roles.

Steroid biosynthesis by the ovary. In the theca, under the influence of LH, cholesterol is converted to pregnenolone and metabolised through a series of substrates ending in androgen production. The two-cell, two-gonadotrophin model comes into play with androgens produced by the theca cells transported to the granulosa cells where they are aromatised to oestrogens.

The structure of nuclear hormone receptors. These receptors are composed of 5 structure-function domains labelled A-F (Mangelsdorf et al., 1995) The N-terminal region contains domains A/B, the DNA binding domain (DBD) contains domain C, the hinge region contains domain D and the ligand binding domain (LBD) at the C-terminal end contains domains E/F. Transactivation domains AF1 and AF2 are found in the N-terminal region and the LBD, respectively (White & Parker 1998).


28.2 How Hormones Work

In this section, you will explore the following questions:

Connection for AP ® Courses

Much of the information in this section is an application of the material we explored in the Cell Communication chapter about cell communication and signaling pathways. Hormones are chemical signals (ligands) that mediate changes in target cells by binding to specific receptors. Even though hormones released by endocrine glands can travel long distances through the blood and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Depending on the location of the receptor on the target cell and the chemical structure of the hormone, for example, whether or not it is lipid-soluble, hormones can mediate changes directly by binding to intracellular hormone receptors and modulating gene expression (transcription and translation), or indirectly by binding to cell surface receptors and simulating signaling pathways.

The hormone binds to its receptor like a key fits a lock. Because a lipid-derived hormone such as a steroid hormone can diffuse across the membrane of the target cell, they bind to intracellular receptors residing in the cytoplasm or in the nucleus. The cell signaling pathways induced by steroid hormones regulate specific genes by acting as transcription regulators. In turn, this affects the amount of protein produced. Lipid-derived hormones that are not steroids, for example, vitamin D and thyroxin, bind to receptors located in the nucleus of the target cell.

Because amino acid-derived hormones (with the exception of thyroxine) and polypeptide hormones are not lipid-soluble, they bind to plasma membrane hormone receptors located on the outer surface of the membrane. Unlike steroid hormones, they cannot act directly on DNA but activate a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. The hormone that initiated the signaling pathway is called a first messenger. In the case of the epinephrine signaling pathway, binding of the amino acid-derived hormone epinephrine to its receptor activates a G-protein which, in turn, activates cAMP, a second messenger, ultimately resulting in a cellular response such as the conversion of glycogen to glucose.

Information presented and the examples highlighted in the section support concepts outlined in Big Idea 3 of the AP ® Biology Curriculum Framework. The AP ® Learning Objectives listed in the Curriculum Framework provide a transparent foundation for the AP ® Biology course, an inquiry-based laboratory experience, instructional activities, and AP ® exam questions. A learning objective merges required content with one or more of the seven science practices.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting and receiving chemical signals.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with a cellular response.
Science Practice 1.5 The student can re-express key elements of natural phenomena across multiple representations in the domain.
Learning Objective 3.36 The student is able to describe a model that expresses the key elements of signal transduction pathways by which a signal is converted to a cellular response.

Hormones mediate changes in target cells by binding to specific hormone receptors. 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 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 that 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.

Receptor binding alters cellular activity and results in an increase or decrease in normal body processes. Depending on the location of the protein receptor on the target cell and the chemical structure of the hormone, hormones can mediate changes directly by binding to intracellular hormone receptors and modulating gene transcription, or indirectly by binding to cell surface receptors and stimulating signaling pathways.

Intracellular Hormone Receptors

Lipid-derived (soluble) hormones such as steroid hormones diffuse across the membranes of the endocrine cell. Once outside the cell, they bind to transport proteins that keep them soluble in the bloodstream. At the target cell, the hormones are released from the carrier protein and diffuse across the lipid bilayer of the plasma membrane of cells. The steroid hormones pass through the plasma membrane of a target cell and adhere to intracellular receptors residing in the cytoplasm or in the nucleus. The cell signaling pathways induced by the steroid hormones regulate specific genes on the cell's DNA. The hormones and receptor complex act as transcription regulators by increasing or decreasing the synthesis of mRNA molecules of specific genes. This, in turn, determines the amount of corresponding protein that is synthesized by altering gene expression. This protein can be used either to change the structure of the cell or to produce enzymes that catalyze chemical reactions. In this way, the steroid hormone regulates specific cell processes as illustrated in Figure 28.5.


SuperFoods to Feed Steroid Hormones

The food contains a high amount of human steroids. So they are the building blocks of hormonal growth in human health. The steroid hormones carry main chemicals. These are DHT, OHPC, 17-alpha-estradiol, and estriol. The natural steroids in food along with the 17-alpha-estradiol promote the male sexual aspects.

Foods which promote steroid hormones are as follows:

Spinach

Spinach is rich in vitamins, minerals, chlorophyll, and nitrates. This leafy green improves blood flow and relaxes the blood vessels. Further, it contains the sex nutrient folate and is a potent source of magnesium.

Soy

Soy contains high levels of isoflavones genistein, daidzein, glycoside and so on. This bears impact on the sex hormone metabolism. Flaxseed, tofu, soy milk, etc are rich in phytoestrogen.

Oysters

They are a great source of zinc and aid blood flow to sexual organs. Oysters and scallops contain aphrodisiac compounds. And these can raise the testosterone and estrogen levels.

Quinoa

Quinoa contains arginine, zinc, and magnesium. And it actively takes part in the synthesis of endogenous testosterone. Rich in saponins it is a source of plant steroids.

Avocado

The avocado is rich in MUFAs. This fat lowers the blood cholesterol levels. Further, the plant sterols in this fruit contain estrogen and progesterone.

Wild oats

Wild oats are full of saponins. It boosts the luteinizing hormone and testosterone. The high levels of avenocosides in it release the testosterone bound to proteins.

Egg yolks

Raw eggs arouse the libido. High in vitamins B6 and 5 it regulates the hormone level and fights stress. What’s more, it fights erectile dysfunction as well.

Bananas

Bananas are full of natural bromelain. And that stimulates testosterone production. Further, it contains large amounts of potassium and vitamin B6. And these regulate the heart system.

Fava Beans

Fava beans are rich in protein which is great for athletes. It contains a high amount of fiber, calcium, phosphorus, magnesium and so on. The L-Dopa content in it fosters the growth of the hormone dopamine.

Asparagus

The asparagus is rich in Vitamin E, folic acid, magnesium, etc. It is a natural aphrodisiac which boosts sex drive. Further, it contains diuretic properties which clear excess water out of the body. What’s more, it has both steroidal saponins and steroid ecdysteroids.

Potatoes

Carbs are vital for boosting testosterone in your body. Potatoes (all kinds) are a great gluten-free source of testosterone boosting carbs and very dense in nutrients as well. So have a stockpile of them and make them your main carb source.

Brazil Nuts

Brazil nuts are full of selenium. Only 100 grams of it contains around 2 grams of selenium which is around 2800% of the daily need. Selenium is directly linked to raised testosterone production (study, study). So taking just a couple of Brazil nuts each day will be enough to please you selenium and T needs.

As a man, you should mostly eat often foods that increase testosterone. And make sure to avoid those who promote estrogen.


Steroid and Hormone Abuse

Hormone abuse by adults and children is a serious concern. Recent studies show that 4.2% of all high school males and 2.9% of high school females report having taken anabolic steroids without a doctor&rsquos prescription. Anabolic steroids are related to testosterone, the major male hormone. Abuse of this hormone can lead to physical and psychological side effects. These problems include breast development and hair loss among men, and facial hair growth, menstrual problems and a deepened voice in women. The possible long-term health effects can be serious: liver tumors, abnormal cholesterol levels and heart disease, and stunted height among adolescents. High doses have been related to irritable and aggressive behavior.

Hormones are substances produced by glands (or organs) that regulate bodily functions and behavior. Steroid hormones are one type that are chemically similar to each other, but may have different biological functions. For example, the adrenal glands produce an anti-inflammatory steroid similar to cortisone. These steroids may be prescribed to treat asthma, rashes, and various kinds of swelling or inflammation.

Another kind of steroid is called an anabolic steroid. The term anabolic means building up of a bodily substance, like building bone or muscle. Anabolic steroids given by injection, pill, creams or gels are laboratory forms related to testosterone, which is produced in the testes of men and in the adrenal glands in both men and women. These chemicals are recognized for their effects on building muscle. They are only available by a doctor&rsquos prescription.

Approved Anabloic Steroid Uses

Synthetic (laboratory-made) anabolic steroids have some accepted uses as prescribed medications, but they are best used in specific situations, and, in some cases, for a limited period of time. For example, anabolic steroids can help rebuild tissues that have become weakened because of serious injury or illness. They also can be used to treat certain types of anemia and breast cancer or to replace testosterone among men who do not produce enough of their own testosterone. These drugs can be used to treat a rare genetic problem that causes episodes of swelling, called angioedema.

While anabolic steroids have a beneficial role in the body, these powerful drugs can create serious health risks, especially for our nation's youth, when used in higher doses than the body normally produces. The abuse of anabolic steroids has evolved into a significant health problem in the United States.

Anabolic Steroid Abuse

Anabolic steroids attract young people and adults, who take these drugs to enhance athletic performance and improve their body image. Even though they may take these steroids with good intentions, they may not understand that the drugs are potentially harmful. These problems include aggressive behavior, liver disease, and increased risk of heart disease and certain cancers. Anabolic steroids also can cause permanent undesirable changes in sex characteristics, such as breast growth in men and increased facial hair and deepened voice in women. Among youth who have not attained their natural height, anabolic steroids can stunt their growth. Anabolic steroids should never be taken except while under a doctor's care.

Anabolic steroid use among professional and Olympic athletes is believed to be widespread. Some athletes use steroids to build muscle mass, strength, and speed and to assist in recovery from training and injuries. Others use them to improve their physical appearance.

High-profile athletes who use anabolic steroids may become role models to children and teens because of the athletes' appearance and success in sports. Their use of performance-enhancing substances can influence the behavior of some teens, who begin to use steroids themselves. Although sports can build skills in cooperation, competition, and enhance self-esteem, use of anabolic steroids can harm young athletes' bodies as well as their minds.

In 2015, the Centers for Disease Control and Prevention (CDC) found that 3.5% of all high school students in the United States ad 4.8% of 12th grade males reported using anabolic steroids without a doctor&rsquos prescription. Although males are more likely to have used illegal steroids without a prescription than females, girls are also at risk, especially 9th and 10th grade females whose use during 2015 was 3.4%.

Here are more facts about hormone abuse that you should know:

The CDC's 2011 survey found that nearly 4% of high school students in the United States used anabolic steroid pills or shots without a prescription. Young people can find these drugs from users who are at gyms and sports-training centers, and on the Internet.

Anabolic steroids have been found in over-the-counter supplements, without being identified on the label.

Publications available online and elsewhere give recipes for "stacking" and "cycling." Stacking refers to using several steroids at once. Cycling describes how to use steroids for several weeks and then stop using for several weeks. Easy-to-obtain catalogs and advertisements show how to purchase steroids.

Young people have abused anabolic steroids meant for animals by getting access to veterinary steroids. These steroids are often cheaper and easier to obtain than anabolic steroids designed for people.

Steroid users are often risk-takers who use a variety of harmful substances. 25% of steroid users share needles, which increases the risk of infectious disease.

Some evidence shows that anabolic steroids can be addictive, but more research is needed. There is evidence that large doses of anabolic steroids affect the brain's chemistry and produce mental changes.

Telling youngsters only about the harmful effects of steroids is not enough to stop them. In fact there is evidence that &ldquoscare tactics&rdquo can be counterproductive. This is because young athletes know about professional athletes who have used steroids successfully and look fine. The best approach may be to admit the positive effects of steroids, but discuss the dangerous and permanent consequences of their use.

Anabolic Steroids

Anabolic steroids come in various forms, including pills, creams, patches, tablets, injections (shots), or drops placed under the tongue. Improper use of anabolic steroids can have unhealthy side effects.

Anti-aging Hormones

Hormone Health Network will help you separate myths from facts about these two anti-aging hormones: human growth hormone and DHEA.

Health Effects of Steroids

Unhealthy and damaging effects may result from the use of anabolic steroids that can lead to both emotional and physical problems.o

Steroid Precursors

Anabolic steroid precursors are substances that the body can convert into anabolic steroids. Learn more about anabolic steroid precursors abuse, how supplements and steroid precursors can affect hormone health.

Types of Steroids

Learn about types commonly abused steroids and how to avoid them in supplements.


Content Background: The Biochemistry of Steroids

Steroids 1 are a class of hormones 2 that are synthesized by specific cells or tissues in the body and released into the bloodstream. Steroids are non-polar 3 molecules produced from the precursor cholesterol. Four interconnected rings of carbon atoms form the skeleton of all steroids (Figure 1). The type of steroid formed is dependent upon the polar 4 hydroxyl groups (OH) attached to the interconnected rings and the synthesizing tissue. Examples of synthesizing tissues, the corresponding steroids and some of their many functions are listed below.

Adrenal gland
glucocorticoids (cortisol) – maintain blood glucose during stress, anti-inflammatory
mineralocorticoids (aldosterone) – regulate kidney function (water retention)

Ovaries
estrogen – promotes endometrial cell (uterine) proliferation
progesterone – promotes endometrial cell differentiation

Testes
testosterone – stimulates sperm production, promotes muscle growth

Most steroids are used for medicinal purposes, especially the glucocorticoids, which are powerful anti-inflammatory agents. However, due to very serious side effects from long-term use (such as weight gain, bone density loss, increase in blood cholesterol levels, and liver disorders), they are only used as a last resort. Estrogen and progesterone are used in birth control pills and also in post-menopausal women to replace what is lost during aging (this is controversial). Testosterone (Figure 2) is an anabolic steroid, which promotes growth of muscle tissue. “Anabolic” literally means to build up tissue and it refers to the retention of nitrogen atoms in the body reflecting an increase in protein synthesis and/or a decrease in protein breakdown. While testosterone may be used in some clinical situations (e.g. testosterone-deficient men), it (or synthetic versions) is used mainly by body builders to increase muscle growth and by athletes to increase muscle growth and performance. Testosterone, like other steroids, has multiple effects in the body. It not only promotes muscle growth, it is also an androgen 5 . It causes the development of male sexual characteristics such as growth of chest and facial hair, growth of the testes and deepening of the voice (Figure 2). Other effects of testosterone include acne, fluid retention, increased libido, aggression and other psychological disturbances.

Definitions:
1 a class of hormones synthesized from cholesterol by specific cells in the body. They are powerful compounds that alter genetic function, causing numerous effects in the body.
2 chemicals in the body that are synthesized in one tissue and secreted into the bloodstream for actions in tissues some distance away. They regulate many physiologic functions.
3 a chemical property of a substance that indicates an even distribution of charge within the molecule. A non-polar or non-charged compound mixes well with organic solvents and lipids but not with water.
4 a chemical property of a substance that indicates an uneven distribution of charge within the molecule. A polar substance or drug mixes well with water but not with organic solvents and lipids. Polar or charged compounds do not cross cell membranes (lipid) very easily.
5 a steroid hormone such as testosterone that is masculinizing (deepens voice, produces facial & chest hair, sperm production

Figure 1 The general structure of a steroid molecule is shown. Different steroids are defined by the location of polar hydroxyl groups (OH) attached to the C atoms within the rings.

Figure 2 The structure of testosterone is shown. This steroid, synthesized in the testes, has both anabolic and androgenic properties.


SPECIFIC, NONGENOMIC ACTIONS OF STEROID HORMONES

AbstractTraditionally, steroid hormone action has been described as the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid action has been widely recognized only recently. Evidence for these rapid effects is available for steroids of all clones and for a multitude of species and tissues. Examples of nongenomic steroid action include rapid aldosterone effects in lymphocytes and vascular smooth muscle cells, vitamin D3 effects in epithelial cells, progesterone action in human sperm, neurosteroid effects on neuronal function, and vascular effects of estrogens. Mechanisms of action are being studied with regard to signal perception and transduction, and researchers have developed a patchy sketch of a membrane receptor-second messenger cascade similar to those involved in catecholamine and peptide hormone action. Many of these effects appear to involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C, and tyrosine kinases. The physiological and pathophysiological relevance of these effects is unclear, but rapid steroid effects on cardiovascular, central nervous, and reproductive functions may occur in vivo. The cloning of the cDNA for the first membrane receptor for steroids should be achieved in the near future, and the physiological and clinical relevance of these rapid steroid effects can then be established.


Gneet

  • In the positive feedback control an accumulating biochemical increases its own production.
  • For example, uterine contraction at the onset of labour stimulates the release of the hormone, oxytocin, which intensifies uterine contractions.
  • The contraction further stimulate the production of oxytocin. The cycle of increase stops suddenly after the birth of the baby.

Peptide hormone action

  1. Hormone called first messenger attaches to the cell surface receptors proteinon the outer surface of plasma membrane of the target cell, forming a hormone receptor complex.
  2. These complex activates the enzyme adenyl-cyclase
  3. Adenylcyclasecatalyses the conversion of ATD to cyclic AMP(Cyclic adenosine monophosphate or cAMP) on the inner surface of plasma membrane.
  4. cAMP serves as the ‘second messenger’ or intercellular hormonal mediator delivering information inside the target cells. This activates appropriate cellular enzyme by cascade effect. This induces the cell machinery to perform its specialized function.
  5. Ca2+ may be involved along with cAMP.
  6. ) cAMP has a very short existence. It is rapidly degraded by the cAMPphosphodiesterase.

- Water soluble hormones, such as amines, peptides, proteins and glycoproteins exert their control through cyclic AMP. These are quick acting hormones and produce immediate effect.


Contents

Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic. In addition, glucocorticoids play important roles in fetal development and body fluid homeostasis.

Immune Edit

As discussed in more detail below, glucocorticoids function through interaction with the glucocorticoid receptor:

  • up-regulate the expression of anti-inflammatory proteins.
  • down-regulate the expression of proinflammatory proteins.

Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes. This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids. [4]

Metabolic Edit

The name "glucocorticoid" derives from early observations that these hormones were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood.

  • Stimulation of gluconeogenesis, in particular, in the liver: This pathway results in the synthesis of glucose from non-hexose substrates, such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.
  • Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis.
  • Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose
  • Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.
  • Increase in sodium retention and potassium excretion leads to hypernatremia and hypokalemia [5]
  • Increase in hemoglobin concentration, likely due to hindrance of the ingestion of red blood cell by macrophage or other phagocyte. [1]
  • Increased urinary uric acid [6]
  • Increased urinary calcium and hypocalcemia [7]
  • Alkalosis [8]
  • Leukocytosis [9]

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids. [4]

Developmental Edit

Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function. Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival [8] and may also play a role in hippocampal development. Glucocorticoids stimulate the maturation of the Na + /K + /ATPase, nutrient transporters, and digestion enzymes, promoting the development of a functioning gastro-intestinal system. Glucocorticoids also support the development of the neonate's renal system by increasing glomerular filtration.

Arousal and cognition Edit

Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline, these enhance the formation of flashbulb memories of events associated with strong emotions, both positive and negative. [9] This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men). The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in this area of the brain, which has been connected to lower memory performance. [5] [10] [6]

Glucocorticoids have also been shown to have a significant impact on vigilance (attention deficit disorder) and cognition (memory). This appears to follow the Yerkes-Dodson curve, as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern, much like the Yerkes-Dodson curve. For example, long-term potentiation (LTP the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-glucocorticoid state) or after exogenous glucocorticoid administration (high-glucocorticoid state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal. [11] In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information. [7] Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to a lesser extent, after treatment, [12] [13] a condition known as "steroid dementia". [14]

Body fluid homeostasis Edit

Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action to atrial natriuretic peptide (ANP). Centrally, glucocorticoids could inhibit dehydration induced water intake [15] peripherally, glucocorticoids could induce a potent diuresis. [16]

Transactivation Edit

Glucocorticoids bind to the cytosolic glucocorticoid receptor, a type of nuclear receptor that is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements in the promoter region of the target genes resulting in the regulation of gene expression. This process is commonly referred to as transcriptional activation, or transactivation. [17] [18]

The proteins encoded by these up-regulated genes have a wide range of effects, including, for example: [18]

Transrepression Edit

The opposite mechanism is called transcriptional repression, or transrepression. The classical understanding of this mechanism is that activated glucocorticoid receptor binds to DNA in the same site where another transcription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor. [17] [18] While this does occur, the results are not consistent for all cell types and conditions there is no generally accepted, general mechanism for transrepression. [18]

New mechanisms are being discovered where transcription is repressed, but the activated glucocorticoid receptor is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with the function of other transcription factors. This latter mechanism appears to be the most likely way that activated glucocorticoid receptor interferes with NF-κB - namely by recruiting histone deacetylase, which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind. [17] [18]

Nongenomic effects Edit

Activated glucocorticoid receptor has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated glucocorticoid receptor with other proteins or with mRNA. [17] [18]

For example, Src kinase which binds to inactive glucocorticoid receptor, is released when a glucocorticoid binds to glucocorticoid receptor, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, epidermal growth factor, reducing its activity, which in turn results in reduced creation of arachidonic acid - a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect. [17]

A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in both pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water renal physiology). Because they permeate the intestines easily, they are administered primarily per os (by mouth), but also by other methods, such as topically on skin. More than 90% of them bind different plasma proteins, though with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolize by conjugation with a sulfate or glucuronic acid, and are secreted in the urine.

Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary. Cortisol is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol.

The data below refer to oral administration. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not reach the circulation. Fludrocortisone acetate and deoxycorticosterone acetate are, by definition, mineralocorticoids rather than glucocorticoids, but they do have minor glucocorticoid potency and are included in this table to provide perspective on mineralocorticoid potency.

Comparative oral corticosteroid potencies [19] [20] [21]
Name Glucocorticoid potency Mineralocorticoid potency Terminal half-life (hours)
Cortisol (hydrocortisone) 1 1 8
Cortisone 0.8 0.8 8
Prednisone 3.5–5 0.8 16–36
Prednisolone 4 0.8 16–36
Methylprednisolone 5–7.5 0.5 18–40
Dexamethasone 25–80 0 36–54
Betamethasone 25–30 0 36–54
Triamcinolone 5 0 12–36
Fludrocortisone acetate 15 200 24
Deoxycorticosterone acetate 0 20 -
Aldosterone 0.3 200-1000 -
Beclometasone 8 sprays 4 times every day equivalent to orally 14 mg prednisone once a day - -

Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for asthma. They are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes. Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in inflammatory conditions. [22] [23] [24] However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use in tendinopathies. [25]

Physiological replacement Edit

Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12 mg/m 2 /day of hydrocortisone (m 2 refers to body surface area (BSA), and is a measure of body size an average man's BSA is 1.9 m 2 ).

Therapeutic immunosuppression Edit

Glucocorticoids cause immunosuppression, and the therapeutic component of this effect is mainly the decreases in the function and numbers of lymphocytes, including both B cells and T cells.

The major mechanism for this immunosuppression is through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response. [2]

Glucocorticoids suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ, the most important of which is IL-2. Smaller cytokine production reduces the T cell proliferation. [26]

Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in the Bcl-2 gene. [27]

Glucocorticoids also suppress the humoral immunity, thereby causing a humoral immune deficiency. Glucocorticoids cause B cells to express smaller amounts of IL-2 and of IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.

The effect of glucocorticoids on Fc receptor expression in immune cells is complicated. Dexamethasone decreases IFN-gamma stimulated Fc gamma RI expression in neutrophils while conversely causing an increase in monocytes. [28] Glucocorticoids may also decrease the expression of Fc receptors in macrophages, [29] but the evidence supporting this regulation in earlier studies has been questioned. [30] The effect of Fc receptor expression in macrophages is important since it is necessary for the phagocytosis of opsonised cells. This is because Fc receptors bind antibodies attached to cells targeted for destruction by macrophages.

Anti-inflammatory Edit

Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause their primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), [31] the latter effect being much like that of NSAIDs, thus potentiating the anti-inflammatory effect.

In addition, glucocorticoids also suppress cyclooxygenase expression. [32]

Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for rhinitis or inhalers for asthma. These preparations have the advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used are beclometasone, budesonide, fluticasone, mometasone and ciclesonide. In rhinitis, sprays are used. For asthma, glucocorticoids are administered as inhalants with a metered-dose or dry powder inhaler. [33] In rare cases, symptoms of radiation induced thyroiditis has been treated with oral glucocorticoids. [34]

Hyperaldosteronism Edit

Glucocorticoids can be used in the management of familial hyperaldosteronism type 1. They are not effective, however, for use in the type 2 condition.

Resistance Edit

Resistance to the therapeutic uses of glucocorticoids can present difficulty for instance, 25% of cases of severe asthma may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as allergens), immunological phenomena that bypass glucocorticoids, and pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism). [26]

Heart failure Edit

Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics. [35] [36] [37] [38] [39] [40] [41]

Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:

  • Immunodeficiency (see section below) due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance ("steroid diabetes") caution in those with diabetes mellitus
  • Increased skin fragility, easy bruising
  • Negative calcium balance due to reduced intestinal calcium absorption [42] : reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
  • Weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation see corticosteroid-induced lipodystrophy
  • Hypercortisolemia with prolonged or excessive use (also known as, exogenous Cushing's syndrome)
  • Impaired memory and attention deficits [43] (if used for long time and stopped suddenly without a taper) and tendon breakdown (proteolysis), weakness, reduced muscle mass and repair [44][25]
  • Expansion of malar fat pads and dilation of small blood vessels in skin within the epidural space[45]
  • Excitatory effect on central nervous system (euphoria, psychosis) , irregularity of menstrual periods
  • Growth failure, delayed puberty
  • Increased plasma amino acids, increased urea formation, negative nitrogen balance due to increased ocular pressure

In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by 11β-hydroxysteroid dehydrogenase isoenzyme 2 (11β-HSD2) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension, potassium depletion, and metabolic alkalosis.

Immunodeficiency Edit

Glucocorticoids cause immunosuppression, decreasing the function and/or numbers of neutrophils, lymphocytes (including both B cells and T cells), monocytes, macrophages, and the anatomical barrier function of the skin. [46] This suppression, if large enough, can cause manifestations of immunodeficiency, including T cell deficiency, humoral immune deficiency and neutropenia.

  • Enterobacteriaceae including Salmonella species
  • Legionella micdadei
  • Listeria monocytogenes
  • Mycobacterium tuberculosis
  • Nontuberculous mycobacteria
  • Nocardia asteroides
  • Rhodococcus equi
  • Staphylococcus aureus
  • Streptococci
  • Aspergillus
  • Blastomyces
  • Candida species including Candida albicans
  • Coccidioides immitis
  • Cryptococcus neoformans
  • Fusarium species
  • Histoplasma capsulatum
  • Talaromyces marneffei
  • Pneumocystis jirovecii
  • Pseudallescheria boydii
  • Adenovirus
  • Cytomegalovirus
  • Herpes simplex virus
  • Human papillomavirus
  • Influenza/parainfluenza
  • Respiratory syncytial virus
  • Varicella zoster
    /Isospora belli
  • Strongyloides stercoralis
  • Toxoplasma gondii

Withdrawal Edit

In addition to the effects listed above, use of high-dose glucocorticoids for only a few days begins to produce suppression of the patient's adrenal glands suppressing hypothalamic corticotropin-releasing hormone leading to suppressed production of adrenocorticotropic hormone by the anterior pituitary. [19] With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.

During this recovery time, the patient is vulnerable to adrenal insufficiency during times of stress, such as illness. While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example: