ROLE OF CENTRAL NERVOUS SYSTEM AND ENDOCRINE GLANDS IN ADJUSTING OF PHYSIOLOGY FUNCTIONS OF CAVITIES OF MOUTH.
Major endocrine glands. (Male left, female on the right.) 1. Pineal gland 2. Pituitary gland 3. Thyroid gland 4. Thymus 5. Adrenal gland 6. Pancreas 7. Ovary 8. Testis
The endocrine system is a control system of ductless glands that secrete chemical messengers called hormones that circulate within the body via the bloodstream to affect distant cells within specific organs. Endocrine glands secrete their products immediately into the blood or interstitial fluid, without storage of the chemical. Hormones act as “messengers,” and are carried by the bloodstream to different cells in the body, which interpret these messages and act on them. Typical endocrine glands are pituitary, thyroid, and adrenal glands, but not exocrine glands such as salivary glands, sweat glands and glands within the gastrointestinal tract.
Physiology
The endocrine system provides a chemical connection from the hypothalamus of the brain to all the organs that control body metabolism, growth and development, and reproduction
There are two types of hormones secreted in the endocrine system: (1) steroidal and (2) non steroidal, or protein based, hormone
Signal transduction of some hormones with steroid structure involves nuclear hormone receptor proteins that are a class of ligand activated proteins that, when bound to specific sequences of DNA serve as on-off switches for transcription within the cell nucleus. These switches control the development and differentiation of skin, bone and behavioral centers in the brain, as well as the continual regulation of reproductive tissues. They also bind to receptor sites, and activate second messenger systems for more rapid responses. Nonsteroidal hormones bind to receptor sites on the external surface of the cell membrane and use a second messenger method of altering internal cell functions, by altering the pathways already existing in the cells, by activating or deactivating enzymes which modify existing proteins.
The endocrine system regulates its hormones through negative feedback control. Increases in hormone activity decreases the production of that hormone. The immune system and other factors contribute as control factors also, maintaining constant levels of hormones.
Reference: http://www.hormoneprofile.com/howhormoneswork.htm
Endocrine glands and the hormones secreted
· Hypothalamus produces
o Thyrotropin-releasing hormone (TRH)
o Gonadotropin-releasing hormone (GnRH)
o Growth hormone-releasing hormone (GHRH)
o Corticotropin-releasing hormone (CRH)
o Somatostatin (SS; also GHIH, growth factor-inhibiting hormone)
o Dopamine (DA)
· Pineal Gland produces
· Pituitary gland (hypophysis) produces
o Anterior pituitary lobe (adenohypophysis)
§ Growth hormone (GH)
§ Prolactin (PRL)
§ Adrenocorticotropic hormone (ACTH, corticotropin)
§ Thyroid-stimulating hormone (TSH, thyrotropin)
§ Follicle-stimulating hormone (FSH, a gonadotropin)
§ Luteinizing hormone (LH, a gonadotropin)
o Posterior pituitary lobe (neurohypophysis)
§ Oxytocin (ocytocin)
§ Arginine vasopressin (AVP; also ADH, antidiuretic hormone)
· Thyroid gland produces
o Triiodothyronine (T3), the potent form of thyroid hormone
o Thyroxine (T4), a less active form of thyroid hormone
· Parathyroid gland produces
o Parathyroid hormone (PTH)
· Heart produces
o Atrial-natriuretic peptide (ANP)
· Stomach and intestines produce
o Cholecystokinin (CCK)
o Gastrin
o Ghrelin
o Neuropeptide Y (NPY)
o Secretin
· Liver produces
o Insulin-like growth factor (IGF)
· Islets of Langerhans in the pancreas produce
o Insulin
o Glucagon
· Adrenal glands produce
§ Glucocorticoids (chiefly cortisol)
§ Mineralocorticoids (chiefly aldosterone)
§ Androgens (including DHEA and testosterone)
§ Adrenaline (epinephrine)
§ Noradrenaline (norepinephrine)
· Kidney produces
o Renin
o Erythropoietin (EPO)
o Calcitriol (the active form of vitamin D3)
· Skin produces
o Vitamin D3 (calciferol)
o Leptin
In males only
· Testes
o Androgens (chiefly testosterone)
In females only
o Estrogens (mainly estradiol)
o Estrogens (mainly estradiol)
o Human chorionic gonadotropin (HCG)
o Human placental lactogen (HPL)
Ductless gland
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Ductless glands are glands that secrete their product directly onto a surface rather than through a duct. Examples are the goblet cells in the epithelial surface of the digestive, respiratory, urinary and reproductive systems. Many endocrine glands are also ductless glands, as they secrete the hormones they produce directly into the blood or lymph system so it will be circulated to the entire body. The pineal gland, the thymus gland, the pituitary gland, the thyroid gland, the spleen, and the two adrenal glands are all ductless glands.
A gland is an organ in an animal’s body that synthesizes a substance for release such as hormones, often into the bloodstream (endocrine gland) or into cavities inside the body or its outer surface (exocrine gland).
Types of gland
Glands can be divided into two groups:
· Endocrine glands- are glands that secrete their product directly onto a surface rather than through a duct.
· Exocrine glands- secrete their products via a duct, the glands in this group can be divided into three groups:
o Apocrine glands – a portion of the secreting cell‘s body is lost during secretion. Apocrine gland is often used to refer to the apocrine sweat glands.
o Holocrine glands – the entire cell disintegrates to secrete its substances (e.g., sebaceous glands)
o Merocrine glands – cells secrete their substances by exocytosis (e.g., mucous and serous glands). Also called “eccrine.”
The type of secretory product of an Exocrine gland may also be one of three categories:
· Serous glands- secrete a watery, often protein-rich product
· Mucous glands- secrete a viscous product, rich in carbohydrates (e.g., glycoproteins)
· Sebaceous glands- secrete a lipid product
Specific glands
A list of exocrine glands is available here.
A list of endocrine glands is available here.
Additional images
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Section of submaxillary gland of kitten. Duct semidiagrammatic.
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Section of pancreas of dog. X 250.
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Dissection of a lactating breast.
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Section of portion of mamma.
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Hormone
“Hormone” is also the NATO reporting name for the Soviet/Russian Kamov Ka-25 military helicopter.
A hormone (from Greek όρμή – “to set in motion”) is a chemical messenger from one cell (or group of cells) to another. All multicellular organisms produce hormones (including plants – see phytohormone).
The best-known animal hormones are those produced by endocrine glands of vertebrate animals, but hormones are produced by nearly every organ system and tissue type in an animal body. Hormone molecules are secreted (released) directly into the bloodstream; some hormones, called ectohormones, are not secreted into the blood stream, they move by circulation or diffusion to their target cells, which may be nearby cells (paracrine action) in the same tissue or cells of a distant organ of the body. The function of hormones is to serve as a signal to the target cells; the action of hormones is determined by the pattern of secretion and the signal transduction of the receiving tissue.
Most hormones signal a cell change by combining with a receptor. For many hormones, including most protein hormones, the receptor is embedded in the membrane on the surface of the cell. The interaction of the hormone and the receptor typically triggers a cascade of secondary effects within the cytoplasm of the cell, often involving phosphorylation or dephosphorylation of proteins, changes in ion channels, or increased amounts of an intracellular molecule that serves as a second messenger (e.g., cyclic AMP). The second common type of mechanism, typically involving smaller-sized hormones such as steroid or thyroid hormones, begins with entry of the hormone molecule into the cytoplasm of the cell where it combines with a loose and mobile receptor. The combined hormone-receptor ligand then moves across the nuclear membrane into the nucleus of the cell and binds to the DNA, effectively amplifying or suppressing the action of certain genes, thereby affecting protein synthesis.
Hormone effects vary widely, but can include stimulation or inhibition of growth, induction or suppression of apoptosis (programmed cell death), activation or inhibition of the immune system, regulating metabolism and preparation for a new activity (e.g., fighting, fleeing, mating) or phase of life (e.g., puberty, caring for offspring, menopause). In many cases, one hormone may regulate the production and release of other hormones. Many of the responses to hormone signals can be described as serving to regulate metabolic activity of an organ or tissue. Hormones also control the reproductive cycle of virtually all multicellular organisms.
History
The concept of internal secretion developed in the 19th century; Claude Bernard described it in 1855, but did not specifically address the possibility of secretions of one organ acting as messengers to others. Still, various endocrine conditions were recognised and even treated adequately (e.g., hypothyroidism with extract of thyroid glands).
The major breakthrough was the identification of secretin, the hormone secreted by the duodenum that stimulates pancreatic secretions, by Ernest Starling and William Bayliss in 1902. Previously, the process had been considered (e.g., by Ivan Pavlov) to be regulated by the nervous system. Starling and Bayliss demonstrated that injecting duodenal extract into dogs rapidly increased pancreatic secretions in the absence of pancreatic innervation, raising the possibility of a chemical messenger.
Starling is also credited with introducing the term hormone, having coined it in a 1905 Croonian Lecture to the Royal College of Physicians. Later reports indicate it was suggested to him by the Cambridge physiologist William B. Hardy (Henderson 2005).
The remainder of the 20th century saw all the major hormones discovered, as well as the cloning of the relevant genes and the identification of the many interlocking feedback mechanisms that characterize the endocrine system.
Physiology of hormones
Most cells are capable of producing one or more, sometimes many, molecules which signal other cells to alter their growth, function, or metabolism. The classical endocrine glands and their hormone products are specialized to serve regulation on the overall organism level, but can often be used in other ways or only on the tissue level.
The rate of production of a hormone is often regulated by a homeostatic control system, generally by negative feedback. Homeostatic regulation of hormones depends, apart from production, on the metabolism and excretion of hormones.
Hormone secretion can be stimulated and inhibited by:
· Other hormones (stimulating– or releasing-hormones)
· Plasma concentrations of ions or nutrients, as well as binding globulins
· Neurons and mental activity
· Environmental changes, e.g., of light or temperature.
One special group of hormones is the trophic hormones that stimulate the hormone production of other endocrine glands. For example, thyroid-stimulating hormone (TSH) causes growth and increased activity of another endocrine gland, the thyroid, which increases output of thyroid hormones.
A recently-identified class of hormones is that of the “hunger hormones” – ghrelin, orexin and PYY 3-36 – and “satiety hormones” – e.g., leptin, obestatin, nesfatin-1.
Negative feedback
Negative feedback (shortened to NFB) is a type of feedback in which the system responds in an opposite direction to the perturbation. It is a process of feeding back to the input a part of a system‘s output, so as to reverse the direction of change of the output. This tends to keep the output from changing, so it is stabilizing and attempts to maintain constant conditions. This often results in equilibrium (in physical science) or homeostasis (in biology) such that the system will return to its original setpoint automatically.
In contrast, positive feedback is a feedback in which the system responds in the same direction as the perturbation, resulting in amplification of the original signal instead of stablizing the signal. Both positive and negative feedback requires a feedback loop to operate, as opposed to feedforward, which does not rely on a feedback loop for its control of the system.
Examples of the use of negative feedback to control its system are: thermostat control, phase-locked loop, hormonal regulation, and temperature regulation in animals.
Endocrine glands are glands that secrete their product directly onto a surface rather than through a duct. This group contains the glands of the Endocrine system.
Exocrine glands are glands that secrete their products into ducts. They are the counterparts to endocrine glands, which secrete their products directly into the bloodstream.
Types
There are multiple ways of classifying exocrine glands:
Method of secretion
Exocrine glands are named apocrine, holocrine gland, or merocrine gland based on how their product is secreted.
· Apocrine glands – a portion of the plasma membrane buds off the cell, containing the secretion. Apocrine gland is often used to refer to the apocrine sweat glands.
· Holocrine glands – the entire cell disintegrates to secrete its substance.
· Merocrine glands – cells secrete their substances by exocytosis. Also called “eccrine.”
Product secreted
· Serous cells secrete proteins, often enzymes. Examples include chief cells and Paneth cells
· Mucous cells secrete mucus. Examples include Brunner’s glands, esophageal glands, and pyloric glands
· Mixed glands secrete both protein and mucus. Examples include the salivary glands, although parotid gland is predominantly serous, and sublingual gland is predominantly mucous.
Pineal gland
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Pineal gland |
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Endocrine system |
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The pineal gland (also called the pineal body or epiphysis) is a small endocrine gland in the brain. It is located near the center of the brain, between the two hemispheres, tucked in a groove where the two rounded thalamic bodies join. A recent review of the pineal and its secreted hormone, melatonin, is available. [1]
Location
The pineal gland is a greenish-gray body about the size of a pea (8 mm in humans), located just rostro-dorsal to the superior colliculus and behind and beneath the stria medullaris, between the laterally positioned thalamic bodies. It is part of the epithalamus.
The pineal gland is a midline structure, and is often seen in plain skull X-rays, as it is often calcified.
Function
The pineal gland was originally believed to be a “vestigial remnant” of a larger organ (much as the appendix was thought to be a vestigial digestive organ). It was only after the 1960s that scientists discovered that the pineal gland is responsible for the production of melatonin, which is regulated in a circadian rhythm. Melatonin is a derivative of the amino acid tryptophan, which also has other functions in the Central Nervous System. The production of melatonin by the pineal gland is stimulated by darkness and inhibited by light. [7] The retina detects the light, and directly signals and entrains the suprachiasmatic nucleus (SCN). Fibers project from the SCN to the paraventricular nuclei (PVN), which relay the circadian signals to the spinal cord and out via the sympathetic system to superior cervical ganglia (SCG), and from there into the pineal gland.
The pineal gland is large in children, but shrinks at puberty. It appears to play a major role in sexual development, hibernation in animals, metabolism, and seasonal breeding. The abundant melatonin levels in children is believed to inhibit sexual development, and pineal tumors have been linked with precocious puberty. When puberty arrives, melatonin production is reduced. –Calcification of the pineal gland is typical in adults.
Rick Strassman believes that the Pineal Gland also produces the hormone dimethyltryptamine which is present in small quantities in the human body.
Pineal cytostructure seems to have evolutionary similarities to the retinal cells of chordates. [8] Modern birds and reptiles have been found to express the phototransducing pigment melanopsin in the pineal gland. Avian pineal glands are believed to act like the suprachiasmatic nucleus in mammals. [9]
Reports in rodents suggest that the pineal gland may influence the actions of drugs of abuse such as cocaine [10] and antidepressants such as fluoxetine (Prozac)[11]; and contribute to regulation of neuronal vulnerability.[12]
Additional images
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Mesal aspect of a brain sectioned in the median sagittal plane. |
Dissection showing the ventricles of the brain. |
Hind- and mid-brains; postero-lateral view. |
Median sagittal section of brain. |
Melatonin
Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle. In higher animals melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.
Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4] Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[5][6]
Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus of the hypothalamus (SCN) which receives information from the retina about the daily pattern of light and darkness. This signal forms part of the system that regulates the circadian cycle, but it is the SCN that controls the daily cycle in most components of the paracrine and endocrine systems[7][8] rather than the melatonin signal (as was once postulated). Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood, whereas melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
Role as an antioxidant
Although the primary site of melatonin’s action is via the melatonin receptors, melatonin evolved first as an antioxidant, and has only this primitive and primary function in many lower life forms.[12]
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[13]
Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule caeuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as “the free radical scavenging cascade”. This is not true of other, conventional antioxidants.[14]
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[15]
The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson’s disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[16][17][18]
Role in immune system
The body of research is overwhelmingly supportive of the claim that melatonin interacts with the immune system[19]. Melatonin may help fight disease,[20] but its true role in disease treatment is unknown. There have been very few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on very small, incomplete, clinical trials.
Melatonin is an immunoregulator that enhances T cell production somewhat. When taken in conjunction with calcium, it is a very potent immunostimulator of the T cell response. Due to these immunoregulatory effects, it is used as an adjuvant in many clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.
Medical applications
Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at OHSU found that it may ameliorate SAD and circadian misalignment,[21] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[22] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[23]
Melatonin receptors appear to be important in mechanisms of learning and memory,[24] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer’s disease). Thus, melatonin may be effective for treating Alzheimer’s Disease.[25] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer’s, adversely affecting their body’s production of melatonin. Those Alzheimer’s patients with this specific affliction often show heightened afternoon agitation, called “sundowning,” which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[26]
Rozerem (ramelteon) is an agonist with high affinity for both MT1 and MT2 melatonin receptors. This is a newly available prescription medication that can be helpful for insomnia.[citatioeeded]
Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[27]
Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches. [28][29]
There may be other, far-reaching therapeutic uses for melatonin, such as in the treatment of various forms of cancer, HIV, and other viral diseases.[30]
Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather’s Functional Histology.)
Thymus
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Thymus |
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Thymus |
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The thymus of a full-term fetus, exposed in situ. |
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derived from internal mammary artery, superior thyroid artery, and inferior thyroid artery |
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third branchial pouch |
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Function
The thymus plays an important role in the development of the immune system, being the primary site of T cell maturation. The organ is most active between the late stages of gestation and early puberty, when most of the T cells an individual will carry for their lifetime are formed. With the onset of puberty the organ atrophies, gradually shrinking in size and function. The atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity. [2]
In the two thymic lobes, lymphocyte precursors from the bone-marrow become thymocytes, and subsequently mature into T cells. Once mature, T cells emigrate from the thymus and constitute the peripheral T cell repertoire responsible for directing many facets of the adaptive immune system. Loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. [3]. The ability of T cells to recognize foreign antigens is mediated by the T cell receptor. The T cell receptor undergoes genetic rearrangement during thymocyte maturation, resulting in each T cell bearing a unique T cell receptor, specific to a limited set of peptide:MHC combinations. The random nature of the genetic rearrangement results in a requirement of central tolerance mechanisms to remove or inactive those T cells which bear a T cell receptor with the ability to recognise self-peptides.
Phases of thymocyte maturation
The generation of T cells expressing distinct T cell receptors occurs within the thymus, and can be conceptually divided into three phases:
· A rare population of hematopoietic progenitors enters the thymus from the blood, and expands by cell division to generate a large population of immature thymocytes[4].
· Immature thymocytes each make distinct T cell receptors by a process of gene rearrangement. This process is error-prone, and some thymocytes fail to make functional T cell receptors, whereas other thymocytes make T cell receptors that are autoreactive. [5]. Growth factors include thymopoietin and thymosin.
· Immature thymocytes undergo a process of selection, based on the specificity of their T cell receptors. This involves selection of T cells that are functional (positive selection), and elimination of T cells that are autoreactive (negative selection).
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functional (positive selection) |
autoreactive (negative selection) |
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In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC/HLA, to ensure reactivity and specificity[6]. Positive selection eliminates (apoptosis) weak binding cells and only takes high medium binding cells. (Binding refers to the ability of the T-cell receptors to bind to either MHC class I/II or peptide molecules.) |
Negative selection is not 100% complete. Some autoreactive T cells escape thymic censorship, and are released into the circulation. Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells. If these central tolerance mechanisms also fail, autoimmunity may arise. |
Cells that pass both levels of selection are released into the bloodstream to perform vital immune functions.
Atrophy
The thymus continues to grow between birth and puberty and then begins to atrophy, a process directed by the high levels of circulating sex hormones. Proportional to thymic size, thymic activity (T cell output) is most active before puberty. Upon atrophy, the size and activity are dramatically reduced, and the organ is primarily replaced with fat (a phenomenon known as “involution”). The atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity. [8]
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about 15 grams; |
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about 35 grams |
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twenty-five years |
25 grams |
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sixty years |
less than 15 grams |
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seventy years |
about 6 grams |
Structure
Histology
Minute structure of thymus.
Each lateral lobe is composed of numerous lobules held together by delicate areolar tissue; the entire gland being enclosed in an investing capsule[9] of a similar but denser structure. The primary lobules vary in size from that of a pin’s head to that of a small pea, and are made up of a number of small nodules or follicles.
The follicles are irregular in shape and are more or less fused together, especially toward the interior of the gland. Each follicle is from 1 to 2 mm in diameter and consists of a medullary and a cortical portion[10], and these differ in many essential particulars from each other.
Cortex
The cortical portion is mainly composed of lymphoid cells, supported by a network of finely-branched epithelial reticular cells, which is continuous with a similar network in the medullary portion. This network forms an adventitia to the blood vessels.
The cortex is the location of the earliest events in thymocyte development, where T cell receptor gene rearrangement and positive selection takes place.
Medulla
In the medullary portion, the reticulum is coarser than in the cortex, the lymphoid cells are relatively fewer iumber, and there are found peculiar nest-like bodies, the concentric corpuscles of Hassall.[11] These concentric corpuscles are composed of a central mass, consisting of one or more granular cells, and of a capsule formed of epithelioid cells. They are the remains of the epithelial tubes, which grow out from the third branchial pouches of the embryo to form the thymus. Each follicle is surrounded by a vascular plexus, from which vessels pass into the interior, and radiate from the periphery toward the center, forming a second zone just within the margin of the medullary portion. In the center of the medullary portion there are very few vessels, and they are of minute size.
The medulla is the location of the latter events in thymocyte development. Thymocytes that reach the medulla have already successfully undergone T cell receptor gene rearrangement and positive selection, and have been exposed to a limited degree of negative selection. The medulla is specialised to allow thymocytes to undergo additional rounds of negative selection to remove auto-reactive T cells from the mature repertoire. The gene AIRE is expressed in the medulla, and drives the transcription of organ-specific genes such as insulin to allow maturing thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex.
Thymus in medicine
Since many decades isolated active ingredients from the thymus gland (thymosine alpha 1, thymosine beta 4, etc.) have also been used successfully in order to treat humans with a low immune defence system.
Pituitary gland
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Pituitary gland |
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Located at the base of the skull, the pituitary gland is protected by a bony structure called the sella turcica of the sphenoid bone. |
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Median sagittal through the hypophysis of an adult monkey. Semidiagrammatic. |
The pituitary gland, or hypophysis, is an endocrine gland about the size of a pea that sits in a small, bony cavity (pituitary fossa) covered by a membrane. The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone at the base of the brain.
The pituitary gland secretes hormones regulating homeostasis, including trophic hormones that stimulate other endocrine glands. It is functionally connected to the hypothalamus by the median eminence.
Posterior pituitary (neurohypophysis)
The posterior lobe is connected to a part of the brain called the hypothalamus via the infundibulum (or stalk), giving rise to the tuberoinfundibular pathway. Hormones are made ierve cell bodies positioned in the hypothalamus, and these hormones are then transported down the nerve cell’s axons to the posterior pituitary. Hypothalamic neurons fire such hormones, releasing them into the capillaries of the pituitary gland.
The hormones secreted by the posterior pituitary are
· Oxytocin comes from the paraventricular nucleus in the Hypothalamus
· Antidiuretic hormone (ADH – also known as vasopressin and AVP, arginine vasopressin), comes from the supraoptic nucleus in the Hypothalamus
Anterior pituitary (Adenohypophysis)
The anterior lobe is derived from the oral ectoderm and is composed of glandular epithelium. The anterior pituitary is functionally linked to the hypothalamus via the hypophysial-portal vascular connection in the pituitary stalk. Through this vascular connection the hypothalamus integrates stimulatory and inhibitory central and peripheral signals to the five phenotypically distinct pituitary cell types.
The anterior pituitary hormones, and the hypothalamic hormones that modulate their release are listed below, along with the associated cell types.
The hypothalamic hormones travel to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophyseal portal system.
There is also an interaction between the hormones from the hypothalamus, i.e. TRH induces the release of prolactin.
The control of hormones from the pituitary is in a negative feedback loop. Their release is inhibited by increasing levels of hormones from the target gland on which they act.
Intermediate lobe
There is also an intermediate lobe in many animals. For instance in fish it is believed to control physiological colour change. In adult humans it is just a thin layer of cells between the anterior and posterior pituitary, nearly indistinguishable from the anterior lobe. The intermediate lobe produces melanocyte-stimulating hormone (MSH), although this function is often (imprecisely) attributed to the anterior pituitary.
Functions
The pituitary gland helps control the following body processes:
· Growth
· Some aspects of pregnancy and childbirth
· Breast milk production
· Sex organ functions in both women and men
· Thyroid gland function
· The conversion of food into energy (metabolism)
· Water and osmolarity regulation in the body
Additional images
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Pituitary and pineal glands |
Endocrine system |
The arteries of the base of the brain. |
Mesal aspect of a brain sectioned in the median sagittal plane. |
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Sagittal section of nose mouth, pharynx, and larynx. |
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Thyroid
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Thyroid |
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Endocrine system |
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Thyroid and parathyroid. |
For other uses, see Thyroid cartilage.
The thyroid (from the Greek word for “shield”, after its shape) is one of the larger endocrine glands in the body. It is a double-lobed structure located in the neck and produces hormones, principally thyroxine (T4) and triiodothyronine (T3), that regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body. The hormone calcitonin is also produced and controls calcium blood levels. Iodine is necessary for the production of both hormones. Hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid) are the most common problems of the thyroid gland. Specialists are called Thyroidologists.
Blood supply
Blood supply
The thyroid gland is supplied by two pairs of arteries: the superior and inferior thyroid arteries of each side. The superior thyroid artery is the first branch of the external carotid, and supplies mostly the upper half of the thyroid gland, while the inferior thyroid artery is the major branch of the thyrocervical trunk, which comes off of the subclavian artery. In 10% of people, there is an additional thyroid artery, the thyreoidea ima, that arises from the brachiocephalic trunk or the arch of the aorta. Lymph drainage follows the arterial supply.
There are three main veins that drain the thyroid to the superior vena cava: the superior, middle and inferior thyroid veins.
In comparison to the other organs of the body, the Thyroid receives one of the largest blood supplies per gram weight.[citatioeeded] The largest blood supply is seen in the Carotid arch baroreceptor organ.[citatioeeded]
Embryologic development
Floor of pharynx of embryo between 18 and 21 days.
The thyroid is derived from the second pharyngeal arch. In the fetus, at 3-4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue between the tuberculum impar and the copula at a point latter indicated by the foramen cecum. Subsequently the thyroid descends in front of the pharyngeal gut as a bilobed diverticulum through the thyroglossal duct. Over the next few weeks, it migrates to the base of the neck. During migration, the thyroid remains connected to the tongue by a narrow canal, the thyroglossal duct.
Follicles of the thyroid begin to make colloid in the 11th week and thyroxine by the 18th week.
Physiology
The primary function of the thyroid is production of the hormones thyroxine (T4), triiodothyronine (T3), and calcitonin. Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is about ten times more active than T4[1].
T3 and T4 production and action
Thyroxine is synthesised by the follicular cells from free tyrosine and on the tyrosine residues of the protein called thyroglobulin (TG). Iodine, captured with the “iodine trap” by the hydrogen peroxide generated by the enzyme thyroid peroxidase (TPO)[2] and linked to the 3′ and 5′ sites of the benzene ring of the tyrosine residues on TG, and on free tyrosine. Upon stimulation by TSH (see below), the follicular cells reabsorb TG and proteolytically cleave the iodinated tyrosines from TG, forming T4 and T3 (in T3, one iodine is absent compared to T4), and releasing them into the blood. Deiodinase enzymes convert T4 to T3[3]. Thyroid hormone that is secreted from the gland is about 90% T4 and about 10% T3[1].
Cells of the brain are a major target for thyroid hormone. Thyroid hormones play a particularly crucial role in brain development during pregnancy[4]. A transport protein (OATP1C1) has been identified that seems to be important for T4 transport across the blood brain barrier[5]. A second transport protein (MCT8) is important for T3 transport across brain cell membranes[5].
In the blood, T4 and T3 are partially bound to thyroxine-binding globulin, transthyretin and albumin. Only a very small fraction of the circulating hormone is free (unbound) – T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. As with the steroid hormones and retinoic acid, thyroid hormones cross the cell membrane and bind to intracellular receptors (α1, α2, β1 and β2), which act alone, in pairs or together with the retinoid X-receptor as transcription factors to modulate DNA transcription[1].
T3 and T4 regulation
The production of thyroxine is regulated by thyroid-stimulating hormone (TSH), released by the anterior pituitary. The thyroid and thyrotropes form a negative feedback loop: TSH production is suppressed when the T4 levels are high, and vice versa. The TSH production itself is modulated by thyrotropin-releasing hormone, which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones (estrogen and testosterone), and excessively high blood iodide concentration.
Calcitonin
An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cells produce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone. However calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid, but not the parathyroids.
It may be used diagnostically as a tumor marker for a form of thyroid cancer (medullary thyroid adenocarcinoma), in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g. swollen lymph nodes) to establish whether they are metastasis of the original cancer.
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
The significance of iodine
In areas of the world where iodine (essential for the production of thyroxine, which contains four iodine atoms) is lacking in the diet, the thyroid gland can be considerably enlarged, resulting in the swolleecks of endemic goitre.
Thyroxine is critical to the regulation of metabolism and growth throughout the animal kingdom. Among amphibians, for example, administering a thyroid-blocking agent such as propylthiouracil (PTU) can prevent tadpoles from metamorphosing into frogs; conversely, administering thyroxine will trigger metamorphosis.
In humans, children born with thyroid hormone deficiency will have physical growth and development problems, and brain development can also be severely impaired, in the condition referred to as cretinism. Newborn children in many developed countries are now routinely tested for thyroid hormone deficiency as part of newborn screening by analysis of a drop of blood. Children with thyroid hormone deficiency are treated by supplementation with synthetic thyroxine, which enables them to grow and develop normally.
Because of the thyroid’s selective uptake and concentration of what is a fairly rare element, it is sensitive to the effects of various radioactive isotopes of iodine produced by nuclear fission. In the event of large accidental releases of such material into the environment, the uptake of radioactive iodine isotopes by the thyroid can, in theory, be blocked by saturating the uptake mechanism with a large surplus of non-radioactive iodine, taken in the form of potassium iodide tablets. While biological researchers making compounds labelled with iodine isotopes do this, in the wider world such preventive measures are usually not stockpiled before an accident, nor are they distributed adequately afterward. One consequence of the Chernobyl disaster was an increase in thyroid cancers in children in the years following the accident. [2]
The use of iodised salt is an efficient way to add iodine to the diet. It has eliminated endemic cretinism in most developed countries, and some governments have made the iodination of flour mandatory. Potassium iodide and Sodium iodide are the most active forms of supplemental iodine.
Thyroid hormone
The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis is iodine. The major form of thyroid hormone in the blood is thyroxine (T4). The ratio of T4 to T3 released in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a).
Function
The thyronines act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body’s sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
The thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals. One effect of administering the thyronamines is a severe drop in body temperature.
Related diseases
Both excess and deficiency of thyroxine can cause disorders.
· Thyrotoxicosis or hyperthyroidism is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men.
· Hypothyroidism is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.
· Clinical depression can sometimes be caused by hypothyroidism[1]. Some research[2] has shown that T3 is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.
Medical use of thyroid hormones
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the gut, so can be given orally. Levothyroxine, the most commonly used synthetic thyroxine form, is a stereoisomer of physiological thyroxine, which is metabolised more slowly and hence usually only needs once-daily administration. Natural desiccated thyroid hormones, which are derived from pig thyroid glands, are a “natural” hypothyroid treatment containing 20% T3 and traces of T2, T1 and calcitonin.
Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.
Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.
Effects of thyroxine
· Increased cardiac output
· Increased heart rate
· Increased ventilation rate
· Increased basal metabolic rate
· Development of brain
· Thickens endometrium
Triiodothyronine
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Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone.Thyroid hormone similar to thyroxine but with one less iodine atom per molecule and produced in smaller quantity. It exerts the same biological effects as thyroxine but is more potent
Calcitonin
Calcitonin is a 32 amino acid polypeptide hormone that is produced in humans primarily by the C cells of the thyroid, and in many other animals in the ultimobranchial body.
Physiology
The hormone participates in calcium (Ca2+) and phosphorus metabolism and it was found in fish, reptiles, birds and mammals. In many ways, calcitonin has the counter effects of parathyroid hormone (PTH).
Specifically, calcitonin reduces blood Ca2+ levels in three ways:
· Decreasing Ca2+ absorption by the intestines
· Decreasing osteoclast activity in bones
· Decreasing Ca2+ and phosphate reabsorption by the kidney tubules
Its actions, broadly, are:
· Bone mineral metabolism
o Prevent postprandial hypercalcemia resulting from absorption of Ca2+ from foods during a meal
o Promote mineralization of skeletal bone
o Protect against Ca2+ loss from skeleton during periods of Ca2+ stress such as pregnancy and lactation
· Vitamin D regulation
· A satiety hormone
o Inhibit food intake in rats and monkeys
o May have CNS action involving the regulation of feeding and appetite
The receptor for calcitonin is a G protein-coupled receptor which is coupled by Gs to adenylyl cyclase and thereby to the generation of cAMP in target cells.
Adrenal gland
Overview
Anatomically, the adrenal glands are located in the abdomen, situated on the anteriosuperior aspect of the kidneys. In humans, the adrenal glands are found at the level of the 12th thoracic vertebra and receive their blood supply from the adrenal arteries.
It is separated into two distinct structures, both of which receive regulatory input from the nervous system.
· As its name suggests, the adrenal medulla is at the center of the adrenal gland surrounded by the adrenal cortex. The adrenal medulla is the body’s main source of the catecholamine hormones adrenaline (epinephrine) and noradrenaline (norepinephrine).
· By contrast, some cells of the adrenal cortex belong to the hypothalamic-pituitary-adrenal axis and are the source of cortisol synthesis. Other cortical cells produce androgens such as testosterone, while some regulate water and electrolyte concentrations by secreting aldosterone.
Hormones
The adrenal glands secrete steroids, including some sex hormones, and catecholamines. Steroids are synthesized and secreted by the adrenal cortex, while catecholamines are synthesized and secreted by chromaffin cells of the adrenal medulla.
· The principal steroids are aldosterone (a mineralocorticoid) and cortisol (a glucocorticoid).
o Aldosterone promotes sodium retention and potassium excretion and is therefore important in maintaining fluid balance and blood pressure.
o Cortisol on the other hand has a wide range of metabolic effects such as protein and fat breakdown that aim to elevate blood glucose levels.
· Many sex hormones are secreted including testosterone and oestrogen. The sex hormone that is secreted by the adrenals that has the most influence is dehydroepiandrosterone (DHEA). It has virilising effects and is important in development and maintenance of pubic hair, axillary hair, pubertal growth spurts, and sex drive. The effects are only significant in females as the effects are masked by high testosterone levels in males.
· Catecholamines that the adrenal glands secrete are adrenaline and noradrenaline. Adrenaline has the more influential effects. The effects of adrenaline and noradrenaline are wide ranging; adrenaline has a more marked effect on the heart and metabolic activities while noradrenaline is involved more in peripheral vasoconstriction. Adrenaline and noradrenaline secretion is stimulated directly by sympathetic neurons in response to stressors.
The adrenal glands secrete other hormones as well.
Additional images
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Abdominal portion of the sympathetic trunk, with the celiac and hypogastric plexuses. |
Posterior abdominal wall. |
Suprarenal glands viewed from the front. |
Suprarenal glands viewed from behind. |
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Above each human kidney is one of the two adrenal glands. |
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Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.
· Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.
· Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney.
Some commoatural hormones are corticosterone (C21H30O4), cortisone (C21H28O5, 17-hydroxy-11-dehydrocorticosterone) and aldosterone.
Effects
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 maintaiormal concentrations of glucose in blood. These effects include:
· Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids 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.
Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is particularly evident when they are administered at pharmacological doses, but also is important iormal immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.
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.
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.
Mode of action
Glucocorticoids bind to the cytosolic glucocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of any of immune genes, including the IL-2 gene.
The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the “wanted” immune and “unwanted” genes regulating the metabolic and cardiovascular functions. Currently, intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system.
Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol. Data refer to oral dosing, except when mentioned. Note that oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Note that fludrocortisone, DOCA, and aldosterone are not considered glucocorticoids and are included in this table to provide perspective on mineralocorticoid potency.
Physiologic replacement of glucocorticoid
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/m2/day (m2 refers to body surface area (BSA) and is a measure of body size; an average man is 1.7 m2).
Immunosuppressive mechanism
Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-γ, the most important of which is the IL-2. Smaller cytokine production reduces the T cell proliferation.
Glucocorticoids also suppress the humoral immunity, causing 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 causes less T lymphocyte cells to be activated.
Since glucocorticoid is a steroid, it regulates transcription factors; another factor it down regulates is the expression of Fc receptors on macrophages, so there is a decreased phagocytosis of opsonised cells.
Antiinflammatory effects
Glucocorticoids influence all types of inflammatory events, no matter what their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes.
Side effects
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. These are the side effects that could be prevented:
· immunosuppression
· hyperglycemia due to increased gluconeogenesis, insulin resistance and impaired glucose tolerance (“steroid diabetes“); caution in those with diabetes mellitus
· increased skin fragility, easy bruising
· reduced bone density (osteoporosis, higher fracture risk, slower fracture repair)
· weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation
· adrenal insufficiency (if used for long time and stopped suddenly without a taper)
· muscle breakdown (proteolysis), weakness; reduced muscle mass and repair
· expansion of malar fat pads and dilation of small blood vessels in skin
· anovulation, irregularity of menstrual periods
· growth failure, pubertal delay
· increased plasma amino acids, increased urea formation; negative nitrogen balance
· excitatory effect on central nervous system
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.
The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing’s syndrome.
Mode of Action
Mineralocorticoids bind to the cytosolic mineralocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many hormone response elements (HRE) in the promoter region of the target genes in the DNA.
The opposite mechanism is called transrepression. The hormone receptor without ligand binding interacts with heat shock proteins and prevents the transcription of targeted genes.
Aldosterone and cortisol have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids. This enzyme, 11-beta hydroxysteroid dehydrogenase type II(Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites. Licorice is known to be an inhibitor of this enzyme and chronic consumption can result in a condition known as pseudohyperaldosteronism.
Synthesis
It is synthesized from cholesterol by aldosterone synthase, which is absent in other sections of the adrenal gland.
Function
It is the sole endogenous member of the class of mineralocorticoids in human (corticosterone in rodent). It functions in two main locations of the kidney:
· at distal tubule: Acting on mineralocorticoid receptors (MR) on principal cells in the distal tubule of the kidney nephron, it increases the permeability of their apical (luminal) membrane to potassium and sodium and activates their basolateral Na+/K+ pumps, stimulating ATP hydrolysis, reabsorbing sodium (Na+) ions and water into the blood, and excreting potassium (K+) ions into the urine.
· at collecting duct: Aldosterone also stimulates H+ secretion by α-intercalated cells in the collecting duct, regulating plasma bicarbonate (HCO3−) levels and its acid/base balance.[1]
Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal to the entire sodium content in human blood under normal GFR (glomerular filtration rate).[2]
Location of receptors
Unlike neuroreceptors, classic steroid receptors are intracellularly located. The aldosterone/MR receptor complex binds on the DNA to specific hormone response element, which leads to gene specific transcription.
Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the epithelial sodium channel, the Na+/K+ pumps and their regulatory proteins serum and glucocorticoid-induced kinase, and channel-inducing factor respectively.
Stimulation of synthesis
Aldosterone synthesis is stimulated by several factors:
· by increased plasma angiotensin II, ACTH, or potassium levels, which are present in proportion to plasma sodium deficiencies.
· by plasma acidosis.
· by the stretch receptors located in the atria of the heart. If decreased blood pressure is detected, the adrenal gland is stimulated by these stretch receptors to release aldesterone, which increases sodium reabsorption from the urine, sweat and the gut. This causes increased osmolarity in the extracellular fluid which will eventually return blood pressure toward normal.
The secretion of aldosterone has a diurnal rhythm.[3]
Control of aldosterone release in the kidney
· The role of the renin-angiotensin system
· The role of sympathetic nerves
· The role of baroreceptors
· The role of the juxtaglomerular apparatus
· The plasma concentration of potassium
Pituitary gland
The pituitary gland, or hypophysis, is an endocrine gland about the size of a pea that sits in a small, bony cavity (pituitary fossa) covered by a membrane. The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone at the base of the brain.
The pituitary gland secretes hormones regulating homeostasis, including trophic hormones that stimulate other endocrine glands. It is functionally connected to the hypothalamus by the median eminence.
Sections
Located at the base of the brain, the pituitary is functionally linked to the hypothalamus. It is divided into two lobes: the anterior or front lobe (adenohypophysis) and the posterior or rear lobe (neurohypophysis).
Posterior pituitary (neurohypophysis)
The posterior lobe is connected to a part of the brain called the hypothalamus via the infundibulum (or stalk), giving rise to the tuberoinfundibular pathway. Hormones are made ierve cell bodies positioned in the hypothalamus, and these hormones are then transported down the nerve cell’s axons to the posterior pituitary. Hypothalamic neurons fire such hormones, releasing them into the capillaries of the pituitary gland.
The hormones secreted by the posterior pituitary are
· Oxytocin comes from the paraventricular nucleus in the Hypothalamus
· Antidiuretic hormone (ADH – also known as vasopressin and AVP, arginine vasopressin), comes from the supraoptic nucleus in the Hypothalamus
Anterior pituitary (Adenohypophysis)
The anterior lobe is derived from the oral ectoderm and is composed of glandular epithelium. The anterior pituitary is functionally linked to the hypothalamus via the hypophysial-portal vascular connection in the pituitary stalk. Through this vascular connection the hypothalamus integrates stimulatory and inhibitory central and peripheral signals to the five phenotypically distinct pituitary cell types.
The anterior pituitary hormones, and the hypothalamic hormones that modulate their release are listed below, along with the associated cell types.
Intermediate lobe
There is also an intermediate lobe in many animals. For instance in fish it is believed to control physiological colour change. In adult humans it is just a thin layer of cells between the anterior and posterior pituitary, nearly indistinguishable from the anterior lobe. The intermediate lobe produces melanocyte-stimulating hormone (MSH), although this function is often (imprecisely) attributed to the anterior pituitary.
Functions
The pituitary gland helps control the following body processes:
· Growth
· Some aspects of pregnancy and childbirth
· Breast milk production
· Sex organ functions in both women and men
· Thyroid gland function
· The conversion of food into energy (metabolism)
· Water and osmolarity regulation in the body
Additional images
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Pituitary and pineal glands |
Endocrine system |
The arteries of the base of the brain. |
Mesal aspect of a brain sectioned in the median sagittal plane. |
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Sagittal section of nose mouth, pharynx, and larynx. |
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See also
Oxytocin (Greek: “quick birth”) is a mammalian hormone that also acts as a neurotransmitter in the brain. In women, it is released mainly after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. Oxytocin is released during orgasm in both sexes. In the brain, oxytocin is involved in social recognition and bonding, and might be involved in the formation of trust between people.
Synthesis, storage and release
Oxytocin is made in magnocellular neurosecretory cells in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and is released into the blood from the posterior lobe of the pituitary gland. Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.
In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin as shown in the inset of the figure; neurophysin is a large peptide fragment of the giant precursor protein molecule from which oxytocin is derived by enzymatic cleavage.
Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.
Peripheral (hormonal) actions
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. Oxytocin receptors are expressed by the myoepithelial cells of the mammary gland, and in both the myometrium and endometrium of the uterus at the end of pregnancy. In some mammals, oxytocin receptors are also found in the kidney and heart.
· Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be ‘let down’ into a collecting chamber, from where it can be extracted by sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituary gland.
· Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition is normal. (Takayanagi 2005)
· Oxytocin is secreted into the blood at orgasm – in both males and females (Carmichael et al 1987). In males, oxytocin may facilitate sperm transport in ejaculation.
· Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More important, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of oxytocin can result in hyponatremia.
· Oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation. (Paquin & Danalache 2002, Jankowski 2004). However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies. (Takayanagi 2005)
Actions of oxytocin within the brain
Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the blood-brain barrier. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally-projecting oxytocieurons, different from those that project to the pituitary gland. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum and brainstem.
· Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats (Gimpl 2001), reflecting actions in the hypothalamus and spinal cord.
· Bonding. In the Prairie Vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males [1]. In people, plasma concentrations of oxytocin have been reported to be higher amongst people who claim to be falling in love. Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans. It has been suggested that deficiencies in oxytocin pathways in the brain might be a feature of autism.
· Maternal behavior. Sheep and rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin sheep females show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. [2]
· Various anti-stress functions. Oxytocin reduces blood pressure and cortisol levels, increasing tolerance to pain, and reducing anxiety. Oxytocin may play a role in encouraging “tend and befriend”, as opposed to “fight or flight“, behavior, in response to stress.
· Increasing trust and reducing fear. In a risky investment game, experimental subjects giveasally administered oxytocin displayed “the highest level of trust” twice as often as the control group. Subjects who were told that they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk-aversion (Kosfeld 2005). Nasally-administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses) (Kirsch 2005). There is no conclusive evidence for access of oxytocin to the brain through intranasal administration, however.
· According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol) and reduces withdrawal symptoms. (Kovacs 1998)
· Certain learning and memory functions are impaired by centrally-administered oxytocin. (Gimpl 2001)
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Oxytocin |
Potential adverse reactions
Oxytocin is relatively safe when used at recommended doses. Potential side effects include:[citatioeeded]
· Central nervous system: Subarachnoid hemorrhage, seizures.
· Cardiovascular: Increased heart rate, blood pressure, systemic venous return, cardiac output, and arrhythmias.
· Genitourinary: Impaired uterine blood flow, pelvic hematoma, tetanic uterine contractions, uterine rupture, postpartum hemorrhage.
Evolution
Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are always located close to each other (less than 15,000 bases apart) on the same chromosome and are transcribed in opposite directions. It is thought that the two genes resulted from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomes (modern members of the Agnatha). (Gimpl 2001)
Hypothalamus
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Brain: Hypothalamus |
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Location of the human hypothalamus |
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Median sagittal section of brain of human embryo of three months. (Hypothalamus visible at center.) |
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The hypothalamus (from Greek ὑποθαλαμος = under the thalamus) is a region of the mammalian brain located below the thalamus, forming the major portion of the ventral region of the diencephalon and functioning to regulate certain metabolic processes and other autonomic activities. The hypothalamus links the nervous system to the endocrine system via the pituitary gland, also known as the “master gland,” by synthesizing and secreting neurohormones, often called releasing hormones, as needed that control the secretion of hormones from the anterior pituitary gland — among them, gonadotropin-releasing hormone (GnRH). The neurons that secrete GnRH are linked to the limbic system, which is primarily involved in the control of emotions and sexual activity. The hypothalamus also controls body temperature, hunger, thirst, and circadian cycles.
Hormones of the hypothalamus
· Corticotropin-releasing hormone (CRH)
· Dopamine
· Gonadotropin-releasing hormone (GnRH)
· Growth hormone releasing hormone (GHRH)
· Somatostatin or Growth hormone inhibiting hormone (GHIH)
· Thyrotropin-releasing hormone (TRH)
· Antidiuretic Hormone (ADH)
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Medial Area |
Lateral Area |
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Anterior |
Medial preoptic nucleus |
Lateral preoptic nucleus |
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Tuberal |
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Posterior |
Mammillary nuclei (part of mammillary bodies) |
See also: ventrolateral preoptic nucleus
Inputs to the hypothalamus
Dienchephalon
The hypothalamus is a very complex region, and even small nuclei within the hypothalamus are involved in many different functions. The paraventricular nucleus for instance contains oxytocin and vasopressin neurons which project to the posterior pituitary, but also contains neurons that regulate ACTH and TSH secretion (which project to the anterior pituitary), gastric reflexes, maternal behavior, blood pressure, feeding, immune responses, and temperature.
The hypothalamus co-ordinates many seasonal and circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms, and many important stereotyped behaviours. The hypothalamus must therefore respond to many different signals, some of which are generated externally and some internally. The hypothalamus is thus richly connected with many parts of the CNS, including the brainstem reticular formation and autonomic zones, the limbic forebrain (particularly the amygdala, septum, diagonal band of Broca, and the olfactory bulbs, and the cerebral cortex).
The hypothalamus is responsive to:
· Light: daylength and photoperiod for generating circadian and seasonal rhythms
· Olfactory stimuli, including pheromones
· Steroids, including gonadal steroids and corticosteroids
· Neurally transmitted information arising in particular from the heart, the stomach, and the reproductive tract
· Autonomic inputs
· Blood-borne stimuli, including leptin, ghrelin, angiotensin, insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity etc
· Stress
· Invading microorganisms by increasing body temperature, resetting the body’s thermostat upward.
Steroids
The hypothalamus contains neurons that are sensitive to gonadal steroids and glucocorticoids – (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialised glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH secretion.
Neural inputs
The hypothalamus receives many inputs from the brainstem; notably from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. Oxytocin secretion in response to suckling or vagino-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemoreceptors in the carotid sinus and aortic arch, and from low-pressure atrial volume receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal behaviour in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of LH and FSH. Cardiovascular stimuli are carried by the vagus nerve, but the vagus also conveys a variety of visceral information, including for instance signals arising from gastric distension to suppress feeding. Again this information reaches the hypothalamus via relays in the brainstem.
Estrogen and progesterone act by influencing gene expression in particular neurons. To influence gene expression, estrogen binds to an intracellular receptor, and this complex is translocated to the cell nucleus where it interacts with regions of the DNA known as estrogen regulatory elements (EREs). Increased protein synthesis may follow as soon as 30 min later. Thus, for estrogen to influence the expression of a particular gene in a particular cell, the following must occur:
· the cell must be exposed to estrogen
· the cell must express estrogen receptors
· the gene must be one that is regulated by an ERE.
Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly ieurons in the anterior and mediobasal hypothalamus, notably:
· the preoptic area (where LHRH neurons are located)
· the periventricular nucleus (where somatostatin neurons are located)
· the ventromedial hypothalamus (which is important for sexual behavior).
Ieonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, they determine the ability of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life. Thus, if a female rat is injected once with testosterone in the first few days of postnatal life (during the “critical period” of sex-steroid influence), the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a characteristic of females), but will be capable of exhibiting male sexual behaviors (mounting a sexually receptive female). By contrast, a male rat castrated just after birth will be feminized, and the adult will show female sexual behavior in response to estrogen (sexual receptivity, lordosis}.
In primates, the developmental influence of androgens is less clear, and the consequences are less complete. ‘Tomboyism’ in girls might reflect the effects of androgens on the fetal brain, but the sex of rearing during the first 2-3 years is believed by many to be the most important determinant of gender identity, because during this phase either estrogen or testosterone will have permanent effects on either a female or male brain, influencing both heterosexuality and homosexuality.
The paradox is that the masculinizing effects of testosterone are mediated by estrogen. Within the brain, testosterone is aromatized to (estradiol), which is the principal active hormone for developmental influences. The human testis secretes high levels of testosterone from about week 8 of fetal life until 5-6 months after birth (a similar perinatal surge in testosterone is observed in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective, partly because of the high circulating levels of steroid-binding proteins in pregnancy.
Sex steroids are not the only important influences upon hypothalamic development; stress (clarificatioeeded: positive or negative) in early life determines the capacity of the adult hypothalamus to respond to an acute stressor. Unlike gonadal steroid receptors, glucocorticoid receptors are very widespread throughout the brain; in the paraventricular nucleus, they mediate negative feedback control of CRF synthesis and secretion, but elsewhere their role is not well understood.
Anterior pituitary
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Anterior pituitary |
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Pituitary gland. (Most of the orange region is “pars distalis”, but the part at the top is “pars tuberalis”.) |
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Median sagittal through the hypophysis of an adult monkey. Semidiagrammatic. |
The anterior pituitary (also called the adenohypophysis, from Greek adeno, “gland”; hypo, “under”; physis, “growth”; hence, glandular undergrowth) comprises the anterior lobe of the pituitary gland and is part of the endocrine system. Unlike the posterior lobe, the anterior lobe is genuinely glandular, hence the root adeno in its name.
Under the influence of the hypothalamus, the anterior pituitary produces and secretes several peptide hormones that regulate many physiological processes including stress, growth, and reproduction.
Regions
The term “pars distalis” is sometimes used as a synonym for the the anterior pituitary, but this is not quite correct. The anterior pituitary is usually divided into three regions:
· pars distalis (“distal part”) – the majority of the anterior pituitary
· pars tuberalis (“tubular part”) – a sheath extending up from the pars distalis and wrapping around the pituitary stalk
· pars intermedia (“intermediate part”) – sits between the bulk of the anterior pituitary and the posterior pituitary and is often very small in humans
The function of the tuberalis is not well characterized, and most of the rest of this article refers primarily to the distalis.
Hypothalamic releasing and release-inhibiting factors
Hormone secretion from the anterior pituitary gland is regulated by hormones secreted by the hypothalamus. Neuroendocrine neurons in the hypothalamus project axons to the median eminence, at the base of the brain. At this site, these neurons can release substances into small blood vessels that travel directly to the anterior pituitary gland (the hypothalamo-hypophysial portal vessels).
Insulin
VIDEO
http://217.196.164.19/data/teacher/video/anat/Video/INM5S8C.mov
Insulin (from Latin insula, “island”, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary agent in carbohydrate homeostasis, it has effects on fat metabolism and it changes the liver’s activity in storing or releasing glucose and in processing blood lipids, and in other tissues such as fat and muscle. The amount of insulin in circulation has extremely widespread effects throughout the body.
Insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because of an absolute deficiency of the hormone. Patients with type 2 diabetes mellitus have insulin resistance, relatively low insulin production or both; some type 2 diabetics eventually require insulin when other medications become insufficient in controlling blood glucose levels.
Insulin is composed of 51 amino acid residues and has a molecular weight of 5808 Da.
Insulin’s structure varies slightly between species of animal. Insulin from animal sources differs somewhat in regulatory function strength (ie, in carbohydrate metabolism) in humans because of those variations. Porcine (pig) insulin is especially close to the human version.
Discovery and characterization
In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a microscope when he identified some previously un-noticed tissue clumps scattered throughout the bulk of the pancreas. The function of the “little heaps of cells,” later known as the Islets of Langerhans, was unknown, but Edouard Laguesse later suggested that they might produce secretions that play a regulatory role in digestion.
In 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mehring removed the pancreas from a healthy dog to test its assumed role in digestion. Several days after the dog’s pancreas was removed, Minkowski’s animal keeper noticed a swarm of flies feeding on the dog’s urine. On testing the urine they found that there was sugar in the dog’s urine, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by Eugene Opie, when he clearly established the link between the Islets of Langerhans and diabetes: Diabetes mellitus … is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets.
Nobel Prizes
· Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin. Banting, insulted that Best was not mentioned, shared his prize with Best, and MacLeod immediately shared his with Collip. The patent for insulin was sold to the University of Toronto for one dollar.
· The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein to have its structure be completely determined. He was awarded the Nobel Prize in Chemistry in 1958.
· In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of X-ray diffraction studies. She had been awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography.
· Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for insulin.
Structure and production
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
Within vertebrates, the similarity of insulins is very close. Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one. Even insulin from some species of fish is similar enough to human to be effective in humans. The C-peptide of proinsulin (discussed later), however, is very divergent from species to species.
In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans. One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine portion only accounts for 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells.
In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications of proinsulin remove the center portion of the molecule, or C-peptide, from the C- and N- terminal ends of the proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds. Confusingly, the primary sequence of proinsulin goes in the order “B-C-A”, since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.
Actions on cellular and metabolic level
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
The actions of insulin on the global human metabolism level include:
· Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
· Increase of DNA replication and protein synthesis via control of amino acid uptake.
· Modification of the activity of numerous enzymes (allosteric effect).
The actions of insulin on cells include:
· Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes.
· Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids which are converted to triglycerides; lack of insulin causes the reverse.
· Increased esterification of fatty acids – forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse.
· Decreased proteinolysis – forces reduction of protein degradation; lack of insulin increases protein degradation.
· Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
· Decreased gluconeogenesis – decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
· Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
· Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption.
· Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.
Regulatory action on blood glucose
Despite long intervals between meals or the occasional consumption of meals with a substantial carbohydrate load (e.g., half a birthday cake or a bag of potato chips), human blood glucose levels normally remain within a narrow range. In most humans this varies from about 70 mg/dl to perhaps 110 mg/dl (3.9 to 6.1 mmol/litre) except shortly after eating when the blood glucose level rises temporarily. This homeostatic effect is the result of many factors, of which hormone regulation is the most important.
It is usually a surprise to realize how little glucose is actually maintained in the blood, and body fluids. The control mechanism works on very small quantities. In a healthy adult male of 75 kg with a blood volume of 5 litres, a blood glucose level of 100 mg/dl or 5.5 mmol/l corresponds to about 5 g (1/5 ounce) of glucose in the blood and approximately 45 g (1½ ounces) in the total body water (which obviously includes more than merely blood and will be usually about 60% of the total body weight in men). A more familiar comparison may help — 5 grams of glucose is about equivalent to a commercial sugar packet (as provided in many restaurants with coffee or tea).
There are two types of mutually antagonistic metabolic hormones affecting blood glucose levels:
· catabolic hormones (such as glucagon and catecholamines), which increase blood glucose
· and one anabolic hormone (insulin), which decreases blood glucose
Mechanisms which restore satisfactory blood glucose levels after hypoglycemia must be quick, and effective, because of the immediate serious consequences of insufficient glucose (in the extreme, coma, less immediately dangerously, confusion or unsteadiness, amongst many other effects). This is because, at least in the short term, it is far more dangerous to have too little glucose in the blood than too much. In healthy individuals these mechanisms are indeed generally efficient, and symptomatic hypoglycemia is generally only found in diabetics using insulin or other pharmacologic treatment. Such hypoglycemic episodes vary greatly between persons and from time to time, both in severity and swiftness of onset. In severe cases prompt medical assistance is essential, as damage (to brain and other tissues) and even death will result from sufficiently low blood glucose levels.
Mechanism of glucose dependent insulin release
Beta cells in the islets of Langerhans are sensitive to variations in blood glucose levels through the following mechanism (see figure to the right):
· Glucose enters the beta cells through the glucose transporter GLUT2
· Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation
· Dependent on blood glucose levels and hence ATP levels, the ATP controlled potassium channels (K+) close and the cell membranes depolarize
· On depolarisation, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells
· An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
· Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium.
· Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles
· The calcium level also regulates expression of the insulin gene via the calcium responsive element binding protein (CREB).
This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signalling mechanisms controlling this are not fully understood.
Other substances known which stimulate insulin release are acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin, released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). The first of these act similarly as glucose through phospholipase C, while the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via α2-adrenergic agonists such as norepinephrine) inhibits the release of insulin.
When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans’ alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.
Ovary
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Ovary |
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Internal reproductive organs of human female |
For ovary as part of plants see ovary (plants)
Ovaries are Dick-producing reproductive organs found in male organisms. They are part of the vertebrate female reproductive system. Ovaries in females are homologous to testes in males. The term gonads refers to the ovaries in females and testes in males.
Mammalian ovary
Production of eggs (exocrine)
As female mammals develop within the womb, each ovary develops a number of immature eggs associated with groups of other cells called follicles. While mammals were thought to develop their entire supply of eggs prenatally and soon after birth, new evidence from laboratory mice has called this into question, showing that female mice in fact produce new eggs throughout their reproductive lifetime. However, there is no direct evidence showing that human females produce new eggs after birth. As the animal becomes reproductively mature (the process called puberty in humans), eggs will periodically mature and be released from the ovary (a process called ovulation) so that they will be available for fertilization by sperm. A fertilized egg resulting from union with a sperm becomes a zygote and then an embryo as it develops.
In humans, an egg launched from an ovary has to traverse a slight space before entering the fallopian tube and moving gradually down to the uterus. If fertilized, it implants itself into the lining of the uterus and develops as the pregnancy continues. If the fertilized egg settles into the fallopian tube instead of the uterus an ectopic pregnancy will result. Ectopic pregnancy can also happen if a fertilized egg settles onto the cervix or onto the ovary itself, or if a fertilized egg passes through the gap between the ovary and the fallopian tube into the abdomen.
Hormone secretion (endocrine)
Animal and human ovaries also produce various steroid and peptide hormones. Estrogen and progesterone are the most important of these in mammals.
These hormones serve many functions:
· They induce and maintain the physical changes of puberty and the secondary sex characteristics.
· They support maturation of the uterine endometrium in preparation of implantation of a fertilized egg.
· They provide signals to the hypothalamus and pituitary that help maintain the menstrual cycle.
· Estrogen plays an important role in maintaining subcutaneous fat, bone strength, and some aspects of brain function.
Additional images
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Human female internal reproductive anatomy
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Uterus and uterine tubes
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Organs of the female reproductive system.
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Ovary
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An ovary about to release an egg.
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Vessels of the uterus and its appendages, rear view.
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Broad ligament of adult, showing epoöphoron.
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Uterus and right broad ligament, seen from behind.
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Female pelvis and its contents, seen from above and in front.
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Arteries of the female reproductive tract: uterine artery, ovarian artery and vaginal arteries.
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External Links
Testicle
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Testicle |
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Human male reproductive system and adjacent structures |
The testicles, or testes (singular testis), are the male generative glands in animals. Male mammals have two testicles, which are often contained within an extension of the abdomen called the scrotum.
In land mammals, with the exception of the elephant, the testes are located outside of the body, as they are suspended by the spermatic cord and within the scrotum. This is due to the fact that fertile spermatogenesis in mammals is more efficient at a temperature somewhat less than the core body temperature (37 °C or 98.6 °F for humans). The cremasteric muscle is part of the spermatic cord. When this muscle contracts, the cord is shortened and the testicle is moved closer up toward the body, which provides slightly more warmth to maintain optimal testicular temperature. When cooling is required, the cremasteric muscle relaxes and the testicle is lowered away from the warm body and are able to cool. This phenomenon is known as the cremasteric reflex. It also occurs in response to stress (the testicles rise up toward the body in an effort to protect them in a fight), and there are persistent reports that relaxation indicates approach of orgasm. There is a noticeable tendency to also retract during orgasm.
The testicles can also be lifted voluntarily using the pubococcygeus muscle, which partially activates related muscles. This can sometimes be triggered by tightening or sucking in the stomach or abdomen.
Animals other than mammals do not have externalized testicles. Birds, despite having very high core body temperatures have internal testes: it was once theorized that birds used their air sacs to cool the testes internally, but later studies revealed that birds’ testes function at core body temperature.[1] Marine mammals also have internal testes, but it has recently been shown (eg, for dolphins) that they use elaborate vascular networks to provide the necessary temperature lowering for proper operation.
Size and growth
During puberty, the testicles grow in response to the start of spermatogenesis. Size depends on lytic function, sperm production (amount of spermatogenisis present in testis), interstitial fluid, and Sertoli cell fluid production. After puberty, the volume of the testicles can be increased by over 500% as compared to the pre-pubertal size.
Position
It is most common for one testis to hang lower than the other. The percentage of men with a lower hanging right testis or left testis is about equal. This is due to differences in the vascular anatomical structure on the right and left sides.
Function
Like the ovaries (to which they are homologous), testicles are components of both the reproductive system (being gonads) and the endocrine system (being endocrine glands). The respective functions of the testicles are:
· producing sperm (spermatozoa)
· producing male sex hormones, of which testosterone is the best-known
Both functions of the testicle, sperm-forming and endocrine, are under control of gonadotropic hormones produced by the anterior pituitary:
· luteinizing hormone (LH)
· follicle-stimulating hormone (FSH)
Duct system
Under a tough membraneous shell, the tunica albuginea, the testis contains very fine coiled tubes called the seminiferous tubules. The tubes are lined with a layer of cells that, from puberty into old-age, produce sperm cells. The sperm travel from the seminiferous tubules to the rete testis located in the mediastinum testis, to the efferent ducts, and then to the epididymis where newly-created sperm cells mature (see spermatogenesis). The sperm move into the vas deferens, and are eventually expelled through the urethra and out of the urethral orifice through muscular contractions.
Between the seminiferous tubules are special cells called Leydig cells (or “interstitial cells”) where testosterone and other androgens are formed.
Blood supply and lymphatic drainage
Blood supply and lymphatic drainage of the testes and scrotum are distinct:
· The paired testicular arteries arise directly from the abdominal aorta and descend through the inguinal canal, while the scrotum and the rest of the external genitalia is supplied by the internal pudendal artery (itself a branch of the internal iliac artery).
· Lymphatic drainage of the testes follows the testicular arteries back to the paraaortic lymph nodes, while lymph from the scrotum drains to the inguinal lymph nodes.
The Blood-Testis Barrier
Large molecules cannot pass from the blood into the lumen of a seminiferous tubule due to the presence of tight junctions between adjacent Sertoli cells. The spermatogonia are in the basal compartment (deep to the level of the tight junctions) and the more mature forms such as primary and secondary spermatocytes and spermatids are in the adluminal compartment.
The function of the blood-testis barrier (red highlight in diagram above) may be to prevent an auto-immune reaction. Mature sperm (and their antigens) arise long after immune tolerance is established in infancy. Therefore, since sperm are antigenically different than self tissue, a male animal can react immunologically to his own sperm. In fact, he is capable of making antibodies against them.
Injection of sperm antigens causes inflammation of the testis (autoimmune orchitis) and reduced fertility. Thus, the blood-testis barrier may reduce the likelihood that sperm proteins will induce an immune response, reducing fertility and so progeny.
Testicular size
Testicular size as a proportion of body weight varies widely. In the mammalian kingdom, there is a tendency for testicular size to correspond with multiple mates (ie, harems, polygamy). Production of testicular output sperm and spermatic fluid is also larger in polygamous animals, possibly a spermatogenic competition for survival. Elephants are known to have the biggest testicles in the animal kingdom.
Iormal adult human males, testicular size ranges from the lower end of around 14 cm³ to the upper end larger than 35 cm³. Measurement in the living adult is done in two basic ways:
· (1) comparing the testicle with ellipsoids of known sizes (orchidometer).
· (2) measuring the length, depth and width with a ruler, a pair of calipers or ultrasound imaging. The volume is then calculated, e.g., using the formula for the volume of an ellipsoid: 4/3 π × length × width × depth.
Usually right and left testicles are about the same size.
To some extent, it is possible to change testicular size. Short of direct injury or subjecting them to adverse conditions, e.g., higher temperature than they are normally accustomed to, they can be shrunk by competing against their intrinsic hormonal function through the use of externally administered steroidal hormones. Steroids taken for muscle enhancement often have the undesired side effect of testicular shrinkage. Similarly, stimulation of testicular functions via gonadotropic-like hormones may enlarge their size. Testicles may shrink or atrophy during hormone replacement therapy.
Additional images
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Testicle of a cat: 1 Extremitas capitata, 2 Extremitas caudata, 3 Margo epididymalis, 4 Margo liber, 5 Mesorchium, 6 Epididymis, 7 testicular artery and vene, 8 Ductus deferens
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Testis surface
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Testis cross section
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Parathyroid gland
The parathyroid glands are small endocrine glands in the neck, usually located behind the thyroid gland, which produce parathyroid hormone. In rare cases the parathyroid glands are located within the thyroid glands. Most often there are four parathyroid glands but some people have six or even eight.
Physiology
The sole purpose of the parathyroid glands is to regulate the calcium level in our bodies within a very narrow range so that the nervous and muscular systems can function properly.
When blood calcium levels drop below a certain point, calcium-sensing receptors in the parathyroid gland are activated to release hormone into the blood.
Parathyroid hormone is a small protein that takes part in the control of calcium and phosphorus homeostasis, as well as bone physiology.
It then stimulates osteoclasts to break down bone and release calcium into the blood, and increase gastrointestinal calcium absorption.
Additional images
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Scheme showing development of branchial epithelial bodies. I, II, III, IV. Branchial pouches.
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Human parathyroid glands]]
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Growth hormone
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Growth hormone |
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growth hormone 1 |
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Growth hormone (GH or somatotropin) is a 191 amino acid, single chain polypeptide hormone which is synthesised, stored and secreted by the stomatotraph cells within the lateral wings of the anterior pituitary gland, which stimulates growth and cell reproduction in humans and other vertebrate animals.
This article describes human growth hormone physiology, with brief mentions of the diseases of GH deficiency, GH excess (acromegaly and pituitary gigantism), as well as GH treatment, and HGH quackery. Each of these topics is treated more fully in separate articles.
Terminology
Growth hormone (GH) is also called somatropin and somatotropin (British: somatotrophin). hGH refers to human growth hormone and is an abbreviation for human GH measured in the extracts from human pituitary glands. In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. Biosynthetic human growth hormone, also referred to as recombinant human growth hormone, is also called somatropin and abbreviated as rhGH. Since the mid-1990s the abbreviation HGH has begun to carry paradoxical connotations, and now rarely refers to real GH used for indicated purposes. See articles on GH treatment and hGH quackery for fuller discussions of GH therapy and the HGH issue.
Secretion of GH
Several molecular forms of GH circulate. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.
GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency.
Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes.
· Growth hormone releasing hormone (GHRH) from the arcuate nucleus and ghrelin promote GH secretion
· Somatostatin from the periventricular nucleus inhibits it. GH secretion is also affected by negative feedback from circulating concentrations of GH and IGF-1.
Although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion. [1]
· Stimulators of GH secretion include (among others) sleep, exercise, hypoglycemia, dietary protein, and estradiol.
· Inhibitors of GH secretion include dietary carbohydrate and glucocorticoids.
In addition to control by endogenous processes, a number of foreign compounds (xenobiotics) are now known to influence GH secretion and function [2], highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals – see endocrine disruptor.
Secretion patterns
Most of the physiologically important GH secretion occurs as several large pulses or peaks of GH release each day. The plasma concentration of GH during these peaks may range from 5 to 30 ng/mL or more. Peaks typically last from 10 to 30 minutes before returning to basal levels. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Between the peaks, basal GH levels are low, usually less than 3 ng/mL for most of the day and night.
The amount and pattern of GH secretion change throughout life. Basal levels are highest in early childhood. The amplitude and frequency of peaks is greatest during the pubertal growth spurt. Healthy children and adolescents average about 8 peaks per 24 hours. Adults average about 5 peaks. Basal levels and the frequency and amplitude of peaks decline throughout adult life.
Functions of GH
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones GH acts by interacting with a specific receptor on the surface of cells.
Increasing height
Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms.
· 1. GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children’s long bones (arms, legs, digits).
· 2. GH also stimulates production of insulin-like growth factor 1 (IGF1, formerly known as somatomedin C), a hormone homologous to proinsulin.[3] The liver is a major target organ of GH for this process, and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 will also have stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
Other functions
Although height growth is the best known effect of GH, it serves many other metabolic functions as well.
· It increases calcium retention, and strengthens and increases the mineralization of bone.
· It increases muscle mass through the creation of new muscle cells (which differs from hypertrophy)
· It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
· It increases protein synthesis and stimulates the growth of all internal organs excluding the brain.
· It plays a role in fuel homeostasis.
· It reduces liver uptake of glucose, an effect that opposes that of insulin.
· It also contributes to the maintenance and function of pancreatic islets.
· It stimulates the immune system.
Adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH or corticotropin) is a polypeptide hormone synthesised from POMC, (pro-opiomelanocortin) and secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus. It consists of 39 amino acids.
Function
ACTH acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. ACTH stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids (androgens). Together with ACTH the hormones lipotropin, melanocyte-stimulating hormone (MSH), β-endorphin and met-enkephalin are also released. ACTH is also related to the circadian rhythm in many organisms.
Synthetic ACTH
ACTH is available as a synthetic derivative in the form of cosyntropin (synthetic ACTH), tradename Cortrosyn®. It contains the first 24 aminoacids of ACTH but retains full function.[
Thyroid-stimulating hormone
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Thyroid-stimulating hormone, beta |
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Thyroid-stimulating hormone (also known as TSH or thyrotropin) is a hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland.
Physiology
Controlling the rate of release
TSH stimulates the thyroid gland to secrete the hormones thyroxine (T4) and triiodothyronine (T3).[1] TSH production is controlled by a Thyrotropin Releasing Hormone, (TRH), which is manufactured in the hypothalamus and transported to the pituitary gland, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.
The level of Thyroid hormones (T3, T4 and T5) in the blood have an additional effect on the pituitary release of TSH, When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop.
Subunits of TSH
TSH consists of two subunits, the alpha and the beta subunit.
· The α (alpha) subunit is identical to that of human chorionic gonadotropin (HCG), luteinising hormone (LH), follicle-stimulating hormone (FSH).
· The β (beta) subunit is unique to TSH, and therefore determines its function.
The TSH receptor
The TSH receptor is found mainly on thyroid follicular cells. Stimulation of the receptor increases T3 and T4 production and secretion.
Stimulating antibodies to this receptor mimic TSH action and are found in Graves’ disease.
Diagnostic use
TSH levels are tested in the blood of patients suspected of suffering from excess (hyperthyroidism), or deficiency (hypothyroidism) of thyroid homone. Generally, a normal range for TSH is between 0.3 and 3.0 mIU/mL, but the interpretation depends also on what the blood levels of thyroid hormones (T3 and T4) are.
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Source of pathology |
TSH level |
thyroid hormone level |
Disease causing conditions |
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hypothalamus/pituitary |
high |
high |
benign tumor of the pituitary (adenoma) |
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hypothalamus/pituitary |
low |
low |
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thyroid |
low |
high |
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thyroid |
high |
low |
congenital hypothyroidism (cretinism), hypothyroidism or thyroid hormone resistance |
Clearly, both TSH and T3 and T4 should be measured to ascertain where a specific thyroid disfunction is caused by primary pituitary or by a primary thyroid disease. If both are up (or down) then the problem is probably in the pituitary. If the one component (TSH) is up, and the other (T3 and T4) is down, then the disease is probably in the thyroid itself. The same holds for a low TSH, high T3 and T4 finding.
Follicle-stimulating hormone
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Follicle Stimulating Hormone |
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Follicle stimulating hormone, beta polypeptide |
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Follicle stimulating hormone (FSH) is a hormone synthesised and secreted by gonadotropes in the anterior pituitary gland. In the ovary FSH stimulates the growth of immature Graafian follicles to maturation. As the follicle grows it releases inhibin, which shuts off the FSH production. In men, FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes and is critical for spermatogenesis. FSH and LH act synergistically in reproduction.
Structure
FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached to it; two of these make the full, functional protein. Its structure is similar to LH, TSH, and hCG. The protein dimer contains 2 polypeptide units, labelled alpha and beta subunits. The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids. The beta subunits vary. FSH has a beta subunit of 118 amino acids (FSHB) that confers its specific biologic action and is responsible for interaction with the FSH-receptor.The sugar part of the hormone is composed of fructose, galactose, mannose, galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic half-life. The half-life of FSH is 3-4 hours.
Activity
In both males and females, FSH stimulates the maturation of germ cells. In females, FSH initiates follicular growth, specifically affecting granulosa cells. With the concomitant rise in inhibin B FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that seems to be of importance to start the next ovulatory cycle.
Like its partner, LH, FSH release at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH). Those pulses, in turn, are subject to the estrogen feed-back from the gonads.
FSH levels are normally low during childhood and, in women, high after menopause.
High levels of Follicle Stimulating Hormome are indicative of situations where the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. While this is typical in the menopause, it is abnormal in the reproductive years. There it may be a sign of:
2. Gonadal dysgenesis, Turner syndrome
3. Castration
5. Certain forms of CAH
6. Testicular failure
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D cell is visible at upper right, and somatostatinis represented by middle arrow pointing left |
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Somatostatin |
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Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids.
Somatostatin is secreted not only by cells of the hypothalamus but also by delta cells of stomach, intestine, and pancreas. It binds to somatostatin receptors.
Actions
Somatostatin is classified as an inhibitory hormone, whose main actions are to:
· Inhibit the release of growth hormone (GH)
· Inhibit the release of thyroid-stimulating hormone (TSH)
· Suppress the release of gastrointestinal hormones
o Gastrin
o Cholecystokinin (CCK)
o Secretin
o Motilin
o Vasoactive intestinal peptide (VIP)
o Gastric inhibitory polypeptide (GIP)
o Enteroglucagon (GIP)
· Lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine.
· Suppress the release of pancreatic hormones
o Inhibit the release of insulin
o Inhibit the release of glucagon
· Suppress the exocrine secretory action of pancreas.
Somatostatin opposes the effects of Growth Hormone-Releasing Hormone (GHRH)
Synthetic substitutes
Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octopeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. The Food and Drug Administration (FDA) has approved the usage of a salt form of this peptide, octreotide acetate, as an injectable depot formulation for the treatment of acromegaly, the treatment of diarrhea and flushing episodes associated with carcinoid syndrome, and treatment of diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPomas). Octreotide has also been used off-label for the treatment of severe, refractory diarrhea from other causes. It is used in Toxicology for the treatment of prolonged recurrent hypoglycemia after sulfonylurea overdose.
Somatostatin in the brain
Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial portal circulation. These blood vessels carry somatostatin to the anterior pituitary gland, where somatostatin inhibits the secretion of growth hormone from somatotrope cells. The somatostatieurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatieurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone.
Somatostatin is also produced by several other populations that project centrally – i.e. to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there are populations of somatostatieurons in the arcuate nucleus, the hippocampus and the brainstem nucleus of the solitary tract.
Androgen
Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of masculine characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens, which were first discovered in 1936, are also called androgenic hormones or testoids. Androgens are also the original anabolic steroids. They are also the precursor of all estrogens, the female sex hormones. The primary and most well-known androgen is testosterone.
Types of androgens
A subset of androgens, adrenal androgens, includes any of the 19-carbon steroids synthesized by the adrenal cortex, the outer portion of the adrenal gland, that function as weak steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.
Besides testosterone, other androgens include:
· Dehydroepiandrosterone (DHEA): a steroid hormone produced from cholesterol in the adrenal cortex, which is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
· Androstenedione (Andro): an androgenic steroid, which is produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. Use of androstenedione as an athletic or body building supplement has been banned by the International Olympic Committee as well as other sporting organizations.
· Androstenediol: the steroid metabolite that is thought to act as the main regulator of gonadotropin secretion.
· Androsterone: a chemical by-product created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
· Dihydrotestosterone (DHT): a metabolite of testosterone that is actually a more potent androgen in that it binds more strongly to androgen receptors.
Androgen functions
Development of the male
During mammalian development, the gonads are at first capable of becoming either ovaries or testes[1]. In humans, starting at about week 4 the gonadal rudiments are present within intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.
By week 8 of human fetal development, Leydig cells appear in the differentiating gonads of males. The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells which will function to support sperm cell formation. A minor population of non-epithelial cells exists between the tubules, these are the androgen-producing Leydig cells. The Leydig cells can be viewed as producers of androgens that function as paracrine hormones required by the Sertoli cells in order to support sperm production. Soon after they differentiate, Leydig cells begin to produce androgens which are required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, AMH, which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. AMH and androgens cooperate to allow for the normal movement of testes into the scrotum.
Before the production of the pituitary hormone LH by the embryo starting at about weeks 11-12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).
Inhibition of fat deposition
Males typically have less adipose tissue than females. Recent results indicate that androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function[3].
Muscle mass
Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to enhance muscle function by acting on several cell types in skeletal muscle tissue[4].
Brain
Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression[5] and libido.
Insensitivity to androgen in humans
Reduced ability of a XY karyotype fetus to respond to androgens can result in one of several problems, including infertility and several forms of intersex conditions. See androgen insensitivity syndrome (AIS).
Vitamin D
Vitamin D refers to a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 or cholecalciferol.[1] The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains.[1]
Vitamin D plays an important role in the maintenance of several organ systems.[2]
· Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys.
· It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton.
· It inhibits parathyroid hormone secretion from the parathyroid gland.
· Vitamin D affects the immune system by promoting immunosuppression and anti-tumor activity.
Vitamin D deficiency can result from; inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders.[2] Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis.[2]
Forms
Several forms of vitamin D have been described. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.
· Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1
· Vitamin D2: ergocalciferol or calciferol (made from ergosterol)
· Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the skin).
· Vitamin D4: dihydrotachysterol
· Vitamin D5: sitocalciferol (made from 7-dehydrositosterol)
Chemically, the various forms of vitamin D are secosteroids; i.e. broken-open steroids.[3] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–290 nm.[4] These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3.[5] Adequate amounts of vitamin D3 can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated.[1]
In most mammals, including humans, D3 is more effective than D2 at increasing the levels of vitamin D hormone in circulation.[6] However, in some species, such as rats, vitamin D2 is more effective than D3.[7] Both vitamin D2 and D3 are used for humautritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene.[8]
Biochemistry
Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a molecule which does, through a tightly regulated synthesis mechanism.
The epidermal strata of the skin.
Production in the skin
Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The thickness of the epidermis is less than 25μm (.001 inch) thick. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum.[4] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is reduced.
Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths between 270–290 nm and thus the production of vitamin D3 will only occur at those wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum.[4]
Mechanism of action
Once vitamin D is produced in the skin or consumed in food, it requires chemical conversion in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when “D” is used without a subscript it refers to either D2 or D3). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein, plasma vitamin D binding protein (DBP), it is transported to various target organs.[3]
The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[3] The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The VDR belongs to the superfamily of steroid/thyroid hormone receptors .
Vitamin D receptors are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.[10]
The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. [8]
In food
Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet.
In some countries, foods such as milk, yoghurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.[12] In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50.[1]
Fatty fish, such as salmon, are natural sources of vitamin D.
Fortified foods represent the major dietary sources of vitamin D, as very few foods naturally contain significant amounts of vitamin D. Natural sources of vitamin D include:[1]
· Fish liver oils, such as cod liver oil, 1 Tbs. (15 mL) provides 1,360 IU
· Fatty fish, such as:
o Salmon, cooked, 3.5 oz provides 360 IU
o Mackerel, cooked, 3.5 oz, 345 IU
o Sardines, canned in oil, drained, 1.75 oz, 250 IU
o Tuna, canned in oil, 3 oz, 200 IU
o Eel, cooked, 3.5 oz, 200 IU
· One whole egg, 20 IU
· Shiitake mushrooms, one of a few natural sources of vegan and kosher vitamin D (in the form of ergosterol vitamin D2)
Role in immunomodulation
The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects.
Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns. VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.
VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages.[8] Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi.[25] Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.
These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection.[22] However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosis and other diseases involving vitamin D hypersensitivity.
A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D.[30]
