CLINICAL BIOCHEMISTRY

INTRODUCTIONClinical biochemistry is also known as clinical chemistry, chemical pathology, medical biochemistry or pure blood chemistry.

Clinical biochemistry is the area of pathology that is generally concerned with analysis of body fluids.

Biochemical tests including: Tests for various components of blood and

urine. Measurement of the activities of different

enzymes. Spectrometric assay. Electrophoresis. Immunoassay. Endocrinology.

Most current laboratories are now highly automated and use assays that are closely monitored and quality controlled.

Serum is the yellow watery part of blood that is left after blood has been allowed to clot and all blood cells have been removed.

This is most easily done by centrifugation which packs the denser blood cells and platelets to the bottom of the centrifuge tube, leaving the liquid serum fraction resting above the packed cells.

Plasma is essentially the same as serum, but is obtained by centrifuging the blood without clotting. Plasma therefore contains all of the clotting factors, including fibrinogen.

ENDOCRINOLOGYEndocrinology is a branch of medicine dealing with disorder of the endocrine system and its specific secretions (hormones).

Endocrinology is concerned with the study of the: Biosynthesis of hormones Storage of hormones Chemistry of hormones Physiological function of hormones Cells of the endocrine glands Tissues that secrete hormones

The endocrine system consists of several glands, in different parts of the body that secrete hormones directly into the blood rather than into a duct system.

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Hormones have many different functions and modes of action. One hormone may have several effects on different target organs.One target organ may be affected by more than one hormone.

Chemical that classified as a hormone should be: Produced by an organ. Released in small amounts into the blood. Transported by the blood to a distant organ to

exert its specific function.

A hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism.

Three mechanisms of chemical signaling of hormone can be distinguished:1. Autocrine signalingChemical signal acts on the same cell. The cell signals itself through a chemical that it synthesizes and then responds to. This effect can occur within the cytoplasm of the cell or by an interacting with receptors on the surface of the same cell.

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2. Paracrine signalingChemical signals that diffuse into the area and interact with receptors on nearby cells. Paracrine effect is a chemical communication between cells within a tissue or organ, e.g. the release of neurotransmitters at synapses in the nervous system. 3. Endocrine signalingThe chemicals are secreted into the blood and carried to the cells they act upon.A neuroendocrine signal is a "classical" hormone that is released into the blood by a neurosecretory neuron.

Hormones act by binding to specific receptors in the target organ.

Hormone is essentially a chemical messenger that transports a signal from one cell to another. Endocrine hormone molecules are secreted (released) directly into the bloodstream.Exocrine hormone molecules are secreted directly into a duct, and from the duct they either flow into the bloodstream or they flow from cell to cell.

Endocrinology as a profession (job)

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Although every organ system (including the brain, lungs, heart, intestine, skin, and the kidney) secretes and responds to hormones, the clinical specialty of endocrinology focuses primarily on the endocrine organs (the organs whose primary function is hormone secretion).

These endocrine organs include the: pituitary gland thyroid gland adrenal gland ovaries testes pancreas

An endocrinologist is a doctor who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others.The medical specialty of endocrinology involves the diagnostic evaluation of a wide variety of symptoms and variations and the long-term management of disorders of deficiency or excess of one or more hormones.

The diagnosis and treatment of endocrine diseases are guided by laboratory tests to a greater extent than for most specialties.

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Many diseases are investigated through excitation/stimulation or inhibition/suppression Testing. This might involve injection with a stimulating agent to test the function of an endocrine organ. Blood is then sampled to assess the changes of the relevant hormones or metabolites.

Most endocrine disorders are chronic diseases that need life-long care.

Some of the most common endocrine diseases include:

diabetes mellitus hypothyroidism The metabolic syndrome.

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HormoneA hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism.

Hormone is essentially a chemical messenger that transports a signal from one cell to another.

All multi-cellular organisms produce hormones; plant hormones are also called phyto hormones.

Hormones in animals are often transported in the blood. Cells respond to a hormone when they express a specific receptor for that hormone.

The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses.

Endocrine hormone molecules are secreted (released) directly into the bloodstream.

Exocrine hormone (or ecto-hormones) are secreted directly into a duct, and from the duct they either flow into the bloodstream or they flow from cell to

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cell by diffusion in a process known as paracrine signalling.

Chemical classes of hormonesThere are three different classes of hormone based on their chemical composition:

1. AminesAmines, such as nor-epinephrine, epinephrine, and dopamine, are derived from single amino acids, in this case tyrosine.

Thyroid hormones such as 3,5,3’-tri-iodothyronine (T3) and 3,5,3’,5’-tetra-iodothyronine (thyroxine, T4) make up a subset of this class because they derive from the combination of two iodinated tyrosine amino acid residues.

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2. Peptide and proteinPeptide hormones and protein hormones consist of three (in the case of thyrotropin-releasing hormone) to more than 200 (in the case of follicle-stimulating hormone) amino acid residues and can have molecular weights as large as 30,000.

All hormones secreted by the pituitary gland are peptide hormones, as are:

Leptin from adipocytes Ghrelin from the stomach insulin from the pancreas

3. SteroidSteroid hormones are converted from their parent compound, cholesterol.

Vitamin D3 (steroid hormone)

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Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind:

1. Gluco corticoids2. Mineralo corticoids 3. Androgens 4. Estrogens 5. Progestagens

Hormones as a signalHormonal signaling across this hierarchy (chain of commands) involves the following:

1. Biosynthesis of a particular hormone in a particular tissue

2. Storage and secretion of the hormone 3. Transport of the hormone to the target cell(s) 4. Recognition of the hormone by an associated

cell membrane or intracellular receptor protein. 5. Relay (send) and amplification of the received

hormonal signal via a signal transduction process: This then leads to a cellular response. The reaction of the target cells may then be recognized by the original hormone-producing cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback loop.

6. Degradation of the hormone.

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As can be inferred from the hierarchical diagram, hormone biosynthetic cells are typically of a specialized cell type, residing within a particular endocrine gland, such as thyroid gland, ovaries, and testes.

Hormones exit their cell of origin via exocytosis or another means of membrane transport. The hierarchical model is an over simplification of the hormonal signaling process.

Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for insulin, which triggers a diverse (varied) range of systemic physiological affects.

Different tissue types may also respond differently to the same hormonal signal. Because of this, hormonal signaling is elaborate (complicated) and hard to dissect (divided).

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Interactions with receptorsMost hormones initiate a cellular response by initially combining with either a specific intracellular or cell membrane associated receptor protein.

A cell may have several different receptors that recognize the same hormone and activate different signal transduction pathways, or alternatively different hormones and their receptors may invoke (refer to) the same biochemical pathway.

For many hormones, including most protein hormones, the receptor is membrane associated and embedded in the plasma membrane at the surface of the cell.

The interaction of hormone and receptor typically triggers a cascade (flow) of secondary effects within the cytoplasm of the cell, often involving phosphorylation or de-phosphorylation of various other cytoplasmic proteins, changes in ion channel permeability, or increased concentrations of

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intracellular molecules that may act as secondary messengers (e.g. cyclic AMP).

Some protein hormones also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism.

For hormones such as steroid or thyroid hormones, their receptors are located intracellularly within the cytoplasm of their target cell.

In order to bind their receptors these hormones must:

Cross the cell membrane. Combined with receptor. The combined hormone-receptor complex

moves across the nuclear membrane into the nucleus of the cell.

Hormone binds to specific DNA sequences. Hormone is effectively amplifying or

suppressing the action of certain genes. Hormones affecting protein synthesis.

However, it has been shown that not all steroid receptors are located intracellularly, some are plasma membrane associated.

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An important consideration, dictating the level at which cellular signal transduction pathways are activated in response to a hormonal signal is the effective concentration of hormone-receptor complexes that are formed.

Hormone-receptor complex concentrations are effectively determined by three factors:

1. The number of hormone molecules available for complex formation

2. The number of receptor molecules available for complex formation and

3. The binding affinity between hormone and receptor.

The number of hormone molecules available for complex formation is usually the key factor in determining the level at which signal transduction pathways are activated. The number of hormone molecules available being determined by the concentration of circulating hormone, which is in turn influenced by the level and rate at which they are secreted by biosynthetic cells.

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The number of receptors at the cell surface of the receiving cell can also be varied as can the affinity between the hormone and its receptor.

Physiology of hormonesMost cells are capable of producing one or more molecules, which act as signaling molecules to other cells, altering their growth, function, or metabolism.

The classical hormones produced by cells in the endocrine glands are cellular products, specialized to serve as regulators at the overall organism level. They may also exert their effects solely (exclusively) within the tissue in which they are produced and originally released.

We explain before the negative feedback mechanism as the following: Relayed and amplified hormone leads to a cellular response. The reaction of the target cells may then be recognized by the

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original hormone-producing cells, leading to a down-regulation in hormone production.

The rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control mechanism. Such mechanism depends on factors which influence the metabolism and excretion of hormones.

Thus, higher hormone concentration alone cannot trigger the negative feedback mechanism. Negative feedback must be triggered by overproduction of an "effect" of the hormone.

Hormone secretion can be stimulated or 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 TROPIC HORMONES that stimulate the hormone production of other endocrine glands. For example,

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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 such هرمونHHات الجHHوع as ghrelin, orexin and PYY 3-36 - and SATIETY HORMONES such هرمونHHات الشHHبع as leptin, obestatin, nesfatin-1. In order to release active hormones quickly into the circulation, hormone biosynthetic cells may produce and store biologically inactive hormones in the form of pre- or pro-hormones. These can then be quickly converted into their active hormone form in response to a particular stimulus.

Effects of hormoneHormones have the following effects on the body:

stimulation or inhibition of growth mood swings تغيير الحالة المزاجية induction or suppression of apoptosis

(programmed cell death) activation or inhibition of the immune system regulation of metabolism preparation of the body for fighting, sex,

fleeing تجنب, mating, and other activity

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preparation of the body for a new phase of life, such as puberty وغHHالبل , parenting وةHHاألب سن اليأس and menopause , واألمومة

control of the reproductive cycle hunger cravings الرغبة الملحة

A hormone may also regulate the production and release of other hormones.

Hormone signals control the internal environment of the body through homeostasis.

PharmacologyMany hormones and their analogues are used as medication. The most commonly prescribed hormones are:

Estrogens and progestagens (as methods of hormonal contraception منع الحمل).

Thyroxine (as levothyroxine, for hypothyroidism).

Steroids (for autoimmune diseases and several respiratory disorders.

Insulin is used by many diabetics.

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Local preparations for use in otolaryngology often طب األنHHHHHHف واألدن والحنجHHHHHHرة contain pharmacologic equivalents of adrenaline.

Steroid and vitamin D creams are used extensively in dermatological practice.

A "pharmacologic dose" of a hormone is a medical usage referring to an amount of a hormone far greater than naturally occurs in a healthy body.

The effects of pharmacologic doses of hormones may be different from responses to naturally-occurring amounts and may be therapeutically useful. An example is the ability of pharmacologic doses of gluco-corticoid to suppress inflammation.

ENDOCRINE DISEASESA disease due to disorder of the endocrine system is often called a "HORMONE IMBALANCE", but is technically known as an ENDOCRINOPATHY or ENDOCRINOSIS.

Endocrine disease

Classification and external resources

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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. Testes

Among the hundreds of endocrine diseases are:

Adrenal disorders: Addison's disease (hypofunctioning of the

adrenal cortex). It leads to adrenal crisis (disaster) with cardiovascular collapse.

Adrenal hyperplasia.

Mineralo corticoid deficiency .

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Glucose homeostasis disorders: o Diabetes mellitus, is a condition in which the body

either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy. In diabetes, the body either fails to properly respond to its own insulin, does not make enough insulin, or both. This causes glucose to accumulate in the blood, often leading to various complications.

o Hypoglycemia Idiopathic hypoglycemia, is a medical

condition in which the glucose level in the blood (blood glucose ) is abnormally low.

Insulinoma, An insulinoma is a tumour of the pancreas that is derived from beta cell s and secretes insulin .

Metabolic bone disease: o Osteoporosis, is a disease of bone that leads to an

increased risk of fracture . o Osteitis deformans (Paget's disease of bone), is a

general term for inflammation of bone o Rickets and osteomalacia, Osteomalacia term for

the softening of the bones due to defective bone ... Osteomalacia in children is known as rickets

Pituitary gland disorders:

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o Diabetes insipidus, such as diabetes mellitus

o Hypopituitarism o Pituitary tumors

Pituitary adenomas, Pituitary adenomas are tumor s that occur in the pituitary gland , and account for about 10% of intracranial neoplasms

Prolactinoma (or Hyperprolactinemia), A prolactinoma is a benign tumor (adenoma ) of the pituitary gland that produces a hormone called prolactin.

Acromegaly, gigantism, An excess of secretion of growth hormone after puberty can lead to acromegaly

Parathyroid gland disorders: o hyper parathyroidism o Hypo parathyroidism

Sex hormone disorders: o Disorders of sex development or intersex

disorders Gonadal dysgenesis: (the gonads are

ovaries or testes), Gonadal dysgenesis is a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation.It is a type of female hypogonadism in which no functional ovaries are present to induce puberty

o Hypogonadism, Low male or female hormones

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Gonadotropin deficiency , Ovarian failure or Testicular failure.

Ovarian failure Testicular failure

o Disorders of Gender Gender identity disorder, is the formal

diagnosis used by psychologists and physicians to describe persons who experience significant gender dysphoria (discontent with the biological sex they were born with).

o Disorders of Puberty Delayed puberty, described as delayed

puberty when a boy or girl has passed the usual age.

Precocious puberty, is an unusually early onset of puberty, the process of sexual maturation triggered by the brain or exogenous chemicals, which usually begins in late childhood and results in reproductive maturity and completion of growth. Early puberty may be a variation of normal development, or may be a result of a disease or abnormal hormone exposure.

o Menstrual function or fertility disorders

Thyroid disorders: o Goiter , also called a bronchocele, is a swelling in the

thyroid gland, which can lead to a swelling of the neck or larynx (voice box). Goitre usually occurs when the thyroid gland is not functioning properly. Worldwide, the most common cause for goiter is iodine deficiency

o Hyperthyroidism

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o Hypothyroidism, is the disease state in humans and in animals caused by insufficient production of thyroid hormone by the thyroid gland.

o Thyroiditis, is the inflammation of the thyroid gland. o Thyroid cancer

Tumours of the endocrine glands

Hierarchical nature of hormonal controlHormonal regulation of some physiological activities involves a hierarchy (chain of command) of cell types acting on each other either to stimulate or to modulate the release and action of a particular hormone.

The secretion of hormones from successive levels of endocrine cells is stimulated by chemical signals originating from cells higher up the hierarchical system.

The master coordinator of hormonal activity in mammals is the hypothalamus, which acts on input that it receives from the central nervous system.

Other hormone secretion occurs in response to local conditions, such as the rate of secretion of parathyroid hormone by the parathyroid cells in response to fluctuations of ionized calcium levels in extracellular fluid.

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As can be inferred from the hierarchical diagram, hormone biosynthetic cells are typically of a specialized cell type, residing within a particular endocrine gland (e.g., the thyroid gland, the ovaries, or the testes).

Hormones may exit their cell of origin via exocytosis or another means of membrane transport. However, the hierarchical model is an over simplification of the hormonal signaling process. Cellular recipients of a particular hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for insulin, which triggers a diverse range of systemic physiological effects.

Different tissue types may also respond differently to the same hormonal signal. Because of this, hormonal signaling is elaborate and hard to dissect.

The Hormones of the Human:

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Proteins, peptides, and modified amino acidsThese hydrophilic (and mostly large) hormone molecules bind to receptors on the surface of "target" cells; that is, cells able to respond to the presence of the hormone.

These receptors are transmembrane proteins. Binding of the hormone to its receptor initiates a sequence of intracellular signals that may

alter the behavior of the cell (such as by opening or closing membrane channels) or

stimulate (or repress) gene expression in the nucleus by turning on (or off) the promoters and enhancers of the genes.

This is the sequence of events:

The hormone binds to a site on the extracellular portion of the receptor.

o The receptors are transmembrane proteins that pass through the plasma membrane 7 times, with their N-terminal exposed at the exterior of the cell and their C-terminal projecting into the cytoplasm.

Binding of the hormone to the receptor o activates a G protein associated with the

cytoplasmic C-terminal

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o This initiates the production of a "second messenger". The most common of these are

cyclic AMP, (cAMP) which is produced by adenylyl cyclase from ATP,

o The second messenger, in turn, initiates a

series of intracellular events (shown here as short arrows) such as

phosphorylation and activation of enzymes;

release of Ca2+ into the cytosol from stores within the endoplasmic reticulum.

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o In the case of cAMP, these enzymatic changes activate the transcription factor CREB.

o The cell begins to produce the appropriate gene products in response to the hormonal signal it had received at its surface.

Steroid Hormones

Steroid hormones, being hydrophobic molecules, diffuse freely into all cells. However, their "target" cells contain cytoplasmic and/or nuclear proteins that serve as receptors of the hormone.

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The hormone binds to the receptor and the complex binds to hormone response elements - stretches of DNA within the promoters of genes responsive to the hormone.

The hormone/receptor complex acts as a transcription factor turning target genes "on" (or "off").

Hormone RegulationThe levels of hormones circulating in the blood are tightly controlled by three homeostatic mechanisms:

1. When one hormone stimulates the production of a second, the second suppresses the production of the first. Example: The follicle جراب stimulating hormone (FSH) stimulates the release of estrogens from the ovarian follicle. A high level of estrogen, in turn, suppresses the further production of FSH.

2. Antagonistic pairs of hormones. Example: Insulin causes the level of blood sugar (glucose) to drop when it has risen. Glucagon causes it to rise when it has fallen.

3. Hormone secretion is increased (or decreased) by the same substance whose level is decreased (or increased) by the hormone.

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Example: a rising level of Ca2+ in the blood suppresses the production of the parathyroid hormone (PTH). A low level of Ca2+ stimulates it.

Hormone TransportAlthough a few hormones circulate simply dissolved in the blood, most are carried in the blood bound to plasma proteins. For example, all the steroid hormones, being highly hydrophobic, are transported bound to plasma proteins.

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Hormones of the Reproductive SystemFEMALES

The ovaries of sexually-mature females secrete: a mixture of estrogens of which 17β-estradiol

is the most abundant (and most potent). progesterone.

ESTROGENS

Estrogens are steroids. They are primarily responsible for the conversion of

girls into sexually-mature women. development of breasts further development of the uterus and vagina broadening of the pelvis growth of hair increase in adipose (fat) tissue participate in the monthly preparation of the

body for a possible pregnancy participate in pregnancy if it occurs

Estrogens also have non-reproductive effects.

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They antagonize the effects of the parathyroid hormone, minimizing the loss of calcium from bones and thus helping to keep bones strong.

They promote blood clotting.

PROGESTERONEProgesterone is also a steroid. It has many effects in the body. Here we shall focus on the role of progesterone in the menstrual cycle and pregnancy

Regulation of Estrogen and ProgesteroneThe synthesis and secretion of estrogens is stimulated by follicle-stimulating hormone (FSH), which is, in turn, controlled by the hypothalamic gonadotropin releasing hormone (GnRH).

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Hypothalamus

→GnRH

→ Pituitary

→FSH

→Follicle

→Estrogens

High levels of estrogens suppress the release of GnRH (bar) providing a negative-feedback control of hormone levels.

Progesterone production is stimulated by luteinizing hormone (LH), which is also stimulated by GnRH.

Hypothalamus

→GnRH

→ Pituitary

→ LH →Corpus luteum

→Progesterone

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Elevated levels of progesterone control themselves by the same negative feedback loop used by estrogen (and testosterone).

The Menstrual Cycle

About every 28 days, some blood and other products of the disintegration of the inner lining of the uterus (the endometrium بطانة الرحم ) are discharged from the uterus, a process called

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menstruation. During this time a new follicle begins to develop in one of the ovaries. After menstruation ceases, the follicle continues to develop, secreting an increasing amount of estrogen as it does so.

The rising level of estrogen causes the endometrium to become thicker and more richly supplied with blood vessels and glands.

A rising level of LH causes the developing egg within the follicle to complete the first meiotic division (meiosis I), forming a secondary oocyte.

After about two weeks, there is a sudden surge .in the production of LH اندفاع

This surge in LH triggers ovulation: the release of the secondary oocyte البويضة into the fallopian tube.

Under the continued influence of LH, the now-empty follicle develops into a corpus luteum (hence the name luteinizing hormone for LH).

Stimulated by LH, the corpus luteum secretes progesterone which

o continues the preparation of the endometrium for a possible pregnancy

o inhibits the contraction of the uterus o inhibits the development of a new follicle

If fertilization does not occur (which is usually the case),

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o the rising level of progesterone inhibits the release of GnRH which, in turn,

o inhibits further production of progesterone.

As the progesterone level drops, o the corpus luteum begins to degenerate; o the endometrium begins to break down, its

cells committing programmed cell death (apoptosis);

o the inhibition of uterine contraction is lifted, and

o the bleeding and cramps of menstruation begin.

Pregnancy Fertilization of the egg takes place within the fallopian tube. As the fertilized egg passes down the tube, it undergoes its first mitotic divisions. By the end of the week, the developing embryo has become a hollow ball of cells called a blastocyst. At this time, the blastocyst reaches the uterus and embeds itself in the endometrium, a process called implantation. With implantation, pregnancy is established.

The blastocyst has two parts:

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the inner cell mass, which will become the baby, and

the trophoblast, which will o develop into the placenta and umbilical

cord o and begin to secrete human chorionic

gonadotropin (HCG).

HCG is a glycoprotein. It is a dimer of the same alpha subunit (of 89 amino acids)

used by TSH, FSH, and LH) and a unique beta subunit (of 148 amino acids).

HCG behaves much like FSH and LH with one crucial exception: it is NOT inhibited by a rising level of progesterone. Thus HCG prevents the deterioration of the corpus luteum at the end of the fourth week and enables pregnancy to continue beyond the end of the normal menstrual cycle.

Because only the implanted trophoblast makes HCG, its early appearance in the urine of pregnant women provides the basis for the most widely used test for pregnancy (which can provide a positive signal even before menstruation would have otherwise begun).

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As pregnancy continues, the placenta becomes a major source of progesterone, and its presence is essential to maintain pregnancy. Mothers at risk of giving birth too soon can be given a synthetic progestin to help them retain the fetus until it is full-term.

BirthToward the end of pregnancy,

The placenta releases large amounts of CRH which stimulates the pituitary glands of both mother and her fetus to secrete

ACTH , which acts on their adrenal glands causing them to release the estrogen precursor dehydroepiandrosterone sulfate (DHEAS).

This is converted into estrogen by the placenta.

The rising level of estrogen causes the smooth muscle cells of the uterus to

o synthesize connexins and form gap junctions. Gap junctions connect the cells electrically so that they contract together as labor begins.

o express receptors for oxytocin.

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Oxytocin is secreted by the posterior lobe of the pituitary as well as by the uterus.

Prostaglandins are synthesized in the placenta and uterus.

The normal inhibition of uterine contraction by progesterone is turned off by several mechanisms while

both oxytocin and prostaglandins cause the uterus to contract and labor begins.

Three or four days after the baby is born, the breasts begin to secrete milk.

Milk synthesis is stimulated by the pituitary hormone prolactin (PRL), and

its release from the breast is stimulated by oxytocin.

Milk contains an inhibitory peptide. If the breasts are not fully emptied, the peptide accumulates and inhibits milk production. This autocrine action thus matches supply with demand.

Other Hormones

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RelaxinAs the time of birth approaches in some animals (e.g., pigs, rats) , this polypeptide has been found to:

o relax the pubic ligaments o soften and enlarge the opening to the

cervix.

Relaxin is found in pregnant humans but at higher levels early in pregnancy than close to the time of birth. Relaxin promotes angiogenesis, and in humans it probably plays a more important role in the development of the interface between the uterus and the placenta that it does in the birth process.

Activins, Inhibins, Follistatin. These proteins are synthesized within the follicle. Activins and inhibins bind to follistatin. Activins increase the action of FSH; inhibins, as their name suggests, inhibit it. How important they are in humans remains to be seen. However the important role that activin and follistatin play in the embryonic development of vertebrates justifies mentioning them here.

Oral contraceptives: the "pill"

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The feedback inhibition of GnRH secretion by estrogens and progesterone provides the basis for the most widely-used form of contraception. Dozens of different formulations of synthetic estrogens or progestins (progesterone relatives) — or both — are available. Their inhibition of GnRH prevents the mid-cycle surge of LH and ovulation. Hence there is no egg to be fertilized. Usually the preparation is taken for about three weeks and then stopped long enough for normal menstruation to occur.

The main side-effects of the pill stem from an increased tendency for blood clots to form (estrogen enhances clotting of the blood).

RU-486RU-486 (also known as mifepristone) is a synthetic steroid related to progesterone. Unlike the synthetic progestins used in oral contraceptives that mimic the actions of progesterone, RU-486 is a progesterone antagonist; that is, it blocks the action of progesterone. It does this by binding more tightly to the progesterone receptor than progesterone itself but without the normal biological effects:

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The RU-486/receptor complex is not active as a transcription factor.

Thus genes that are turned on by progesterone are turned off by RU-486.

The proteins needed to establish and maintain pregnancy are no longer synthesized.

The endometrium breaks down. The embryo detaches from it and can no longer

make chorionic gonadotropin (HCG). Consequently the corpus luteum ceases its

production of progesterone. The inhibition on uterine contraction is lifted. Soon the embryo and the breakdown products

of the endometrium are expelled.

These properties of RU-486 have caused it to be used to induce abortion of an unwanted fetus. In practice, the physician assists the process by giving a synthetic prostaglandin (e.g., misoprostol [Cytotec®]) 36–48 hours after giving the dose of RU-486. Use of RU-486 is generally limited to the first seven weeks of pregnancy.

RU-486 has been used for many years in some countries. However, the controversies surrounding abortion in the United States kept it from being authorized for use here until September 2000.

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MENOPAUSEThe menstrual cycle continues for many years. But eventually, usually between 42 and 52 years of age, the follicles become less responsive to FSH and LH. They begin to secrete less estrogen. Ovulation and menstruation become irregular and finally cease. This cessation is called menopause.

With levels of estrogen now running one-tenth or less of what they had been, the hypothalamus is released from their inhibitory influence (bar). As a result it now stimulates the pituitary to increased activity. The concentrations of FSH and LH in the blood rise to ten or more times their former values. These elevated levels may cause a variety of unpleasant physical and emotional symptoms.

Hormone replacement therapy (HRT)Many menopausal women elect to take a combination of estrogen and progesterone after they cease to make their own. The benefits are:

reduction in the unpleasant symptoms of the menopause

a reduction in the loss of calcium from bones and thus a reduction in osteoporosis and the fractures that accompany it.

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It was also believed that HRT reduced the risk of cardiovascular disease. However, a recent study of 16,000 menopausal women was stopped 3 years early when it was found that, in fact, HRT increased (albeit only slightly) not decreased the incidence of cardiovascular disease.

Environmental estrogensSome substances that find their way into the environment, such as

DDE, a breakdown product of the once widely-used insecticide DDT,

DDT itself (still used in some countries (e.g., Mexico), and

PCBs, chemicals once used in a wide variety of industrial applications

can bind to the estrogen (and androgen) receptors and mimic (weakly) the effects of the hormone. This has created anxiety that they may be responsible for harmful effects such as cancer and low sperm counts.

However, there is as yet little evidence to support these worries.

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No epidemiological relationship has been found between the incidence of breast cancer and the levels of these compounds in the body.

As for laboratory studies that found a synergistic effect of two of these substances on receptor binding (findings that created the great alarm), these have not been replicated in other laboratories, and the authors of the original report have since withdrawn it as invalid.

MALESThe principal androgen (male sex hormone) is testosterone. This steroid is manufactured by the interstitial (Leydig) cells of the testes. Secretion of testosterone increases sharply at puberty and is responsible for the development of the so-called secondary sexual characteristics (e.g., beard) of men.

Testosterone is also essential for the production of sperm.

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Production of testosterone is controlled by the release of luteinizing hormone (LH) from the anterior lobe of the pituitary gland, which is in turn controlled by the release of GnRH from the hypothalamus. LH is also called interstitial cell stimulating hormone (ICSH).

Hypothalamus

→GnRH

→ Pituitary

→ LH →Testes

→Testosterone

The level of testosterone is under negative-feedback control: a rising level of testosterone suppresses the release of GnRH from the hypothalamus. This is exactly parallel to the control of estrogen secretion in females.

Males need estrogen, too!

Important human hormonesSpelling is not uniform for many hormones. Current North American and international usage is

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estrogen, gonadotropin, while British usage retains the Greek diphthong in oestrogen and the unvoiced aspirant h in gonadotrophin.

Name Abbreviation 

 Effect  

Melatonin (N-acetyl- 5-methoxytryptamine)

antioxidant and causes drowsiness

Serotonin5-HT

Controls mood, appetite, and sleep

Thyroxine (or tetraiodothyronine) (a thyroid hormone)

T4

less active form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines, affect protein synthesis

Triiodothyronine (a thyroid hormone) T3

potent form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines, affect protein synthesis

Epinephrine (or adrenaline)

EPI Fight-or-flight response: Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasodilation, increasing catalysis of glycogen in liver, breakdown of lipids in fat cells. dilate the pupils Suppress non-emergency

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bodily processes (e.g. digestion) Suppress immune system

Norepinephrine (or noradrenaline)

NRE

Fight-or-flight response: Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasoconstriction and increased blood pressure, breakdown of lipids in fat cells. Increase skeletal muscle readiness.

Dopamine (or prolactin inhibiting hormone

DPM, PIH or DA

Increase heart rate and blood pressureInhibit release of prolactin and TRH from anterior pituitary

Antimullerian hormone (or mullerian inhibiting factor or hormone)

AMH Inhibit release of prolactin and TRH from anterior pituitary

Adiponectin Acrp30

Adrenocorticotropic hormone (or corticotropin)

ACTH

synthesis of corticosteroids (glucocorticoids and androgens) in adrenocortical cells

Angiotensinogen and angiotensin

AGT vasoconstriction release of aldosterone from adrenal cortex dipsogen.

Antidiuretic hormone ADH retention of water in kidneys

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(or vasopressin, arginine vasopressin)

moderate vasoconstrictionRelease ACTH in anterior pituitary

Atrial-natriuretic peptide (or atriopeptin)

ANP

CalcitoninCT

Construct bone, reduce blood Ca 2+

Cholecystokinin CCK

Release of digestive enzymes from pancreas Release of bile from gallbladder hunger suppressant

Corticotropin-releasing hormone

CRH Release ACTH from anterior pituitary

Erythropoietin EPOStimulate erythrocyte production

Follicle-stimulating hormone

FSH

In female: stimulates maturation of Graafian follicles in ovary. In male: spermatogenesis, enhances production of androgen-binding protein by the Sertoli cells of the testes

Gastrin GRP Secretion of gastric acid by parietal cells

Ghrelin Stimulate appetite, secretion of growth hormone from anterior pituitary gland

Glucagon GCG glycogenolysis and gluconeogenesis in liver increases blood glucose level

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Gonadotropin-releasing hormone

GnRH Release of FSH and LH from anterior pituitary.

Growth hormone-releasing hormone

GHRH Release GH from anterior pituitary

Human chorionic gonadotropin

hCG

promote maintenance of corpus luteum during beginning of pregnancy Inhibit immune response, towards the human embryo.

Human placental lactogen

HPL

increase production of insulin and IGF-1 increase insulin resistance and carbohydrate intolerance

Growth hormone GH or hGH

stimulates growth and cell reproduction Release Insulin-like growth factor 1 from liver

Inhibin

Insulin INS

Intake of glucose, glycogenesis and glycolysis in liver and muscle from blood intake of lipids and synthesis of triglycerides in adipocytes Other anabolic effects

Insulin-like growth factor (or somatomedin)

IGF insulin-like effects regulate cell growth and development

Leptin LEP decrease of appetite and increase of metabolism.

Luteinizing hormone LH In female: ovulation In male: stimulates Leydig cell production of

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testosterone Melanocyte stimulating hormone

MSH or α-MSH

melanogenesis by melanocytes in skin and hair

Oxytocin OXT

release breast milk. Contraction of cervix and vagina Involved in orgasm, trust between people. and circadian homeostasis (body temperature, activity level, wakefulness).

Parathyroid hormone PTH

increase blood Ca 2+ : *indirectly stimulate osteoclasts

Ca2+ reabsorption in kidney

activate vitamin D (Slightly) decrease blood phosphate:

(decreased reuptake in kidney but increased uptake from bones

activate vitamin D)

Prolactin PRL

milk production in mammary glandssexual gratification after sexual acts

Relaxin RLN Unclear in humans Secretin SCT Secretion of bicarbonate

from liver, pancreas and duodenal Brunner's glands Enhances effects of cholecystokinin Stops

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production of gastric juice

Somatostatin SRIF

Inhibit release of GH and TRH from anterior pituitarySuppress release of gastrin, cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP), enteroglucagon in gastrointestinal systemLowers rate of gastric emptying Reduces smooth muscle contractions and blood flow within the intestine Inhibit release of insulin from beta cells. Inhibit release of glucagon from beta cells . Suppress the exocrine secretory action of pancreas.

Thrombopoietin TPO produce platelets.

Thyroid-stimulating hormone (or thyrotropin)

TSH secrete thyroxine (T4) and triiodothyronine (T3)

Thyrotropin-releasing hormone

TRH Release thyroid-stimulating hormone (primarily)Stimulate prolactin release

Cortisol Stimulation of gluconeogenesis Inhibition of glucose uptake in muscle and adipose tissue Mobilization of amino acids

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from extrahepatic tissues Stimulation of fat breakdown in adipose tissue anti-inflammatory and immunosuppressive

Aldosterone

Increase blood volume by reabsorption of sodium in kidneys (primarily) Potassium and H + secretion in kidney.

Testosterone

Anabolic: growth of muscle mass and strength, increased bone density, growth and strength, Virilizing: maturation of sex organs, formation of scrotum, deepening of voice, growth of beard and axillary hair.

Dehydroepiandrosterone

DHEA Virilization, anabolic

Androstenedione Substrate for estrogenDihydrotestosterone DHT Estradiol E2 Females:

Structural: promote formation of

female secondary sex characteristics

accelerate height growth

accelerate metabolism (burn fat)

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reduce muscle mass stimulate endometrial

growth increase uterine growth maintenance of blood

vessels and skin reduce bone resorption,

increase bone formation Protein synthesis:

increase hepatic production of binding proteins

Coagulation: increase circulating

level of factors 2, 7, 9, 10, antithrombin III, plasminogen

increase platelet adhesiveness

Increase HDL, triglyceride, height growth Decrease LDL, fat depositition Fluid balance:

salt (sodium) and water retention

increase growth hormone

increase cortisol, SHBG Gastrointestinal tract:

reduce bowel motility increase cholesterol in

bile Melanin:

increase pheomelanin,

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reduce eumelanin Cancer: support hormone-sensitive breast cancers [11] Suppression of production in the body of estrogen is a treatment for these cancers.Lung function:

promote lung function by supporting alveoli [12] .

Males: Prevent apoptosis of germ cells[13]

Estrone Estriol Progesterone Support pregnancy:

Convert endometrium to secretory stage Make cervical mucus permeable to sperm. Inhibit immune response, e.g. towards the human embryo. Decrease uterine smooth muscle contractility[14] Inhibit lactation Inhibit onset of labor. Support fetal production of adrenal mineralo- and glucosteroids.Other: Raise epidermal growth factor-1 levels Increase core temperature during ovulation Reduce spasm and relax smooth muscle (widen bronchi and regulate mucus) Antiinflammatory Reduce

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gall-bladder activity Normalize blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy. Assist in thyroid function and bone growth by osteoblasts Relsilience in bone, teeth, gums, joint, tendon, ligament and skin Healing by regulating collagen Nerve function and healing by regulating myelin Prevent endometrial cancer by regulating effects of estrogen.

Calcitriol (1,25-dihydroxy vitamin D3)

Active form of vitamin D3 Increase absorption of calcium and phosphate from gastrointestinal tract and kidneys inhibit release of PTH

Calcidiol (25-hydroxyvitamin D3)

Inactive form of Vitamin D3

Prostaglandins PG Leukotrienes LT Prostacyclin PGI2 Thromboxane TXA2 Prolactin releasing hormone

PRHRelease prolactin from anterior pituitary

Lipotropin PRH lipolysis and steroidogenesis,stimulates melanocytes to

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produce melanin

Brain natriuretic peptide

BNP

(To a minor degree than ANP) reduce blood pressure by: reducing systemic vascular resistance, reducing blood water, sodium and fats

Neuropeptide Y NPYincreased food intake and decreased physical activity

Histaminestimulate gastric acid secretion

EndothelinSmooth muscle contraction of stomach [17]

Pancreatic polypeptide

Unknown

Renin

Activates the renin-angiotensin system by producing angiotensin I of angiotensinogen

Enkephalin Regulate pain

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STEROID HORMONE METABOLISMSteroid hormones can be grouped into five groups by the receptors to which they bind:

1. Glucocorticoids 2. Mineralocorticoids 3. Androgens 4. Estrogens 5. Progestagens

Steroids are lipophilic, low-molecular weight compounds derived from cholesterol that play a number of important physiological roles.

The steroid hormones are synthesized mainly by endocrine glands such as:

The gonads (testes and ovary) The adrenals The fetoplacental unit , during gestation

Steroid hormones act both on peripheral target tissues and the central nervous system (CNS).

An important function of the steroid hormones is to coordinate physiological and behavioural responses for specific biological purposes, e.g. reproduction.

Thus, gonadal steroids influence the sexual differentiation of the genitalia and of the brain,

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determine secondary sexual characteristics during development and sexual maturation, contribute to the maintenance of their functional state in adulthood and control or modulate sexual behaviour.

It has been recently discovered that, in addition to the endocrine glands, the CNS is also able to form a number of biologically active steroids directly from cholesterol (the so-called "NEUROSTEROIDS").

These neurosteroids, however, are more likely to have "autocrine" or "paracrine" functions rather than true endocrine effects.

Despite their relatively simple chemical structure, steroids occur in a wide variety of biologically active forms. This variety is not only due to the large range of compounds secreted by steroid-synthesizing tissues, but also to the fact that circulating steroids are extensively metabolized peripherally, notably in the liver, and in their target tissues, where conversion to an active form is sometimes required before they can elicit their biological responses.

Steroid metabolism is therefore important not only for the production of these hormones, but also for

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the regulation of their cellular and physiological actions.

Structure, nomenclature and classificationThe parent compound from which all steroids are derived is cholesterol.

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As shown before cholesterol is made up of three hexagonal carbon rings (A,B,C) and a pentagonal carbon ring (D) to which a side-chain (carbons 20-27) is attached (at position 17 of the polycyclic hydrocarbon). Two angular methyl groups are also found at position 18 and 19.

Removal of part of the side-chain gives rise to C21-compounds of the pregnane series (progestins and corticosteroids).

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Total removal produces C19-steroids of the androstane series (including the androgens), whereas loss of the 19-methyl group (usually after conversion of the A-ring to a phenolic structure, hence the term "aromatization") yields the estrane series, to which estrogens belong.

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Individual compounds are characterised by the presence or absence of specific functional groups (mainly hydroxy, keto(oxo) and aldehyde functions for the naturally occurring steroids) at certain positions of the carbon skeleton (particularly at positions 3,5,11,17,18,20 and 21).

Given that at most positions, the functional groups can be oriented either in equatorial or axial position, this type of structure gives rise to a great number of possible stereoisomers (i.e. molecules having the same chemical formula, but a different three-dimensional conformation).

Stereoisomerism is very important for biological activity (i.e. for steroid-protein interactions).

Steroid hormone biosynthesis: The adrenals produce both androgens and

corticosteroids (mineralo- and glucocorticoids). The ovaries can secrete estrogens and

progestins. The testis mainly androgens.

However, the biochemical pathways involved are strikingly similar in all tissues, the difference in secretory capacity being mostly due to the presence or absence of specific enzymes. It is therefore possible to give a general outline of the

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major biosynthetic pathways which is applicable to all steroid-secreting glands.

A general outline of the major biosynthetic pathways

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Cholesterol can be synthetized in all steroid-producing tissues from acetate, but the main production sites are the liver, the skin and the intestinal mucosa.

Examples of some routes of steroid metabolism:

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Enzymes involved in steroid biosynthesis: Desmolases (or lyases): these enzymes catalyse

reactions which result in the removal of parts of the original cholesterol side-chain. This involves sequential hydroxylation of adjacent C (e.g., of C-20 and C-22 for P-450scc) and requires a cytochrome P-450, molecular oxygen (O2) and nicotinamide dinucleotide phosphate, reduced form (NADPH) as a cofactor.

Hydroxylases: these enzymes are membrane-bound and are present either in the mitochondrial or in the microsomal fraction of the cell. They also require a

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cytochrome P-450, molecular oxygen and NADPH, as for lyases.

Hydroxysteroid dehydrogenases (oxido-reductases): these enzymes catalyze reversible reactions and depend either on NADP(H) or NAD(H). They are found both in the cell cytosol and in the microsomal fraction.

Aromatase: conversion of the A-ring to a phenolic structure (i.e. with a phenolic HO-group at C-3), a process known as " aromatization ", involves a complex sequence of hydroxylation reactions and loss of the angular C-19 methyl group (10).

Correlation between structure and function: the role of metabolismThe biological activity of a steroid molecule depends on its ability to interact with a specific binding site on the corresponding receptor. In most cases, biological activity can be directly correlated with binding affinity. The affinity (usually characterized by the binding constant KD, which is the molar concentration required to saturate half of the available binding sites) of a steroid for its specific receptor is dependent upon the presence or absence of particular functional groups and the overall three-dimensional structure of the molecule.

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CLINICAL BIOCHEMISTRY, summarySerum is the yellow watery part of blood that is left after blood has been allowed to clot and all blood cells have been removed. This is most easily done by centrifugation which packs the denser blood cells and platelets to the bottom of the centrifuge tube, leaving the liquid serum fraction resting above the packed cells.

Plasma is essentially the same as serum, but is obtained by centrifuging the blood without clotting. Plasma therefore contains all of the clotting factors, including fibrinogen.

Large array of laboratory tests can be sub-categorized into sub-specialties of:

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General or routine chemistry Endocrinology - the study of hormones Immunology - the study of the immune system and antibodies Pharmacology or Toxicology - the study of drugs

Endocrinology is a branch of medicine dealing with: Disorder of the endocrine system and its secretions (hormones). The integration of developmental events such as:

1. proliferation 2. growth 3. differentiation The coordination of metabolism, respiration, excretion,

movement, reproduction, and sensory perception.

Endocrinology is concerned with the study of the: Biosynthesis of hormones Storage of hormones Chemistry of hormones Physiological function of hormones Cells of the endocrine glands Tissues that secrete hormones

The endocrine system consists of several glands, in different parts of the body that secrete hormones directly into the blood rather than into a duct system.

Hormones have many different functions and modes of action; one hormone may have several effects on different target organs, and, conversely, one target organ may be affected by more than one hormone.

Any chemical to be classified as hormone, must be: Produced by an organ. Released in small amounts into the blood. Transported by the blood to a distant organ to exert its specific

function.

A hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism.

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Three mechanisms of chemical signaling of hormone can be distinguished:1. Autocrine signalingChemical signal acts on the same cell. The cell signals itself through a chemical that it synthesizes and then responds to. This effect can occur within the cytoplasm of the cell or by an interacting with receptors on the surface of the same cell.2. Paracrine signalingChemical signals that diffuse into the area and interact with receptors on nearby cells. Paracrine effect is a chemical communication between cells within a tissue or organ, e.g. the release of neurotransmitters at synapses in the nervous system. 3. Endocrine signalingThe chemicals are secreted into the blood and carried to the cells they act upon.A neuroendocrine signal is a "classical" hormone that is released into the blood by a neurosecretory neuron.

Hormone is essentially a chemical messenger that transports a signal from one cell to another. Endocrine hormone molecules are secreted (released) directly into the bloodstream.Exocrine hormone molecules are secreted directly into a duct, and from the duct they either flow into the bloodstream or they flow from cell to cell.

Endocrinology as a profession (job)Although every organ system (including the brain, lungs, heart, intestine, skin, and the kidney) secretes and responds to hormones, the clinical specialty of endocrinology focuses primarily on the endocrine organs (the organs whose primary function is hormone secretion).

These endocrine organs include the pituitary gland, thyroid gland, adrenal gland, ovaries, testes and pancreas.

An endocrinologist is a doctor who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others.

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The diagnosis and treatment of endocrine diseases are guided by laboratory tests to a greater extent than for most specialties.

Many diseases are investigated through excitation/stimulation or inhibition/suppression Testing. This might involve injection with a stimulating agent to test the function of an endocrine organ. Blood is then sampled to assess the changes of the relevant hormones or metabolites. Most endocrine disorders are chronic diseases that need life-long care.

Some of the most common endocrine diseases include: diabetes mellitus hypothyroidism The metabolic syndrome.

There are 3 different classes of hormone based on their chemical composition:1. Amine hormonesAmine hormones, such as nor-epinephrine, epinephrine, and dopamine, are derived from single amino acid (tyrosine).

Thyroid hormones such as 3,5,3’-tri-iodothyronine (T3) and 3,5,3’,5’-tetra-iodothyronine (thyroxine, T4) make up a subset of this class because they derive from the combination of two iodinated tyrosine amino acid residues.

2. Peptide and protein hormonesPeptide and protein hormones consist of 3 to ›200 amino acid residues and have molecular weights as large as 30,000. All hormones secreted by the pituitary gland are peptide hormones. Insuline, liptin, ghrelin are examples for this group.

3. Steroid hormonesSteroid hormones are converted from their parent compound, cholesterol. Vitamin D3, estrogen, progesterone are examples for this group.

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Hormonal signaling caused across hierarchy (chain of commands) involves the following:

7. Biosynthesis of a particular hormone in a particular tissue 8. Storage and secretion of the hormone 9. Transport of the hormone to the target cell(s) 10.Recognition of the hormone by an associated cell membrane or

intracellular receptor protein. 11.Relay (send) and amplification of the received hormonal signal via

a signal transduction process that leads to a cellular response. 12.Degradation of the hormone.

The master coordinator of hormonal activity in mammals is the hypothalamus, which acts on input that it receives from the central nervous system.

Hormones act by binding to specific receptors in the target organ. The receptor has at least two basic constituents:

Recognition site , to which the hormone binds Effector site , which precipitates the modification of cellular

function.

Transduction mechanism of hormone: The hormone binding induces allosteric modification that, in turn, produces the appropriate response.The hormone binds to the receptor protein, resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses.

A cell may have several different receptors that recognize the same hormone and activate different signal transduction pathways.

In order to bind their receptors these hormones must: Cross the cell membrane. Combined with receptor. The combined hormone-receptor complex moves across the

nuclear membrane into the nucleus of the cell. Hormone binds to specific DNA sequences. Hormone is effectively amplifying or suppressing the action of

certain genes. Hormones affecting protein synthesis.

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Hormone-receptor complex concentrations are effectively determined by three factors:

4. The number of hormone molecules available for complex formation

5. The number of receptor molecules available for complex formation and

6. The binding affinity between hormone and receptor.

Hormone secretion can be stimulated or 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

TROPIC HORMONES are special group of 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 (thyroid gland), which increases output of thyroid hormones.

In order to release active hormones quickly into the circulation, hormone biosynthetic cells may produce and store biologically inactive hormones in the form of pre- or pro-hormones. These can then be quickly converted into their active hormone form in response to a particular stimulus (HUNGER HORMONES and SATIETY HORMONES).

The levels of hormones circulating in the blood are tightly controlled by three homeostatic mechanisms:

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4. When one hormone stimulates the production of a second, the second suppresses the production of the first, e.g. FSH hormone stimulates the release of estrogens from the ovaries. A high level of estrogen, in turn, suppresses the further production of FSH.

5. Antagonistic pairs of hormones. Insulin drops the level of blood sugar when it has risen. Glucagon rise the blood sugar level when it has fallen.

6. Hormone secretion is increased (or decreased) by the same substance whose level is decreased (or increased) by the hormone, e.g., a rising level of Ca2+ in the blood suppresses the production of the parathyroid hormone (PTH), while the low level of Ca2+ stimulates the production of PTH.

Hormones have the following effects on the body: stimulation or inhibition of growth mood swings induction or suppression of apoptosis (programmed cell death) activation or inhibition of the immune system regulation of metabolism preparation of the body for a new phase of life, such as puberty ,

parenting , and menopause control of the reproductive cycle regulate the production and release of other hormones.

The most commonly prescribed hormones are: Estrogens and progestagens as methods of hormonal

contraception. Thyroxine for hypothyroidism. Steroids for autoimmune diseases and several respiratory

disorders. Insulin is used by many diabetics. Adrenaline for use in otolaryngology Steroid and vitamin D creams are used extensively in

dermatological practice.

A "pharmacologic dose" of a hormone is a medical usage referring to an amount of a hormone far greater than naturally occurs in a healthy body. The effects of pharmacologic doses of hormones may be different from responses to naturally-occurring amounts and may be

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therapeutically useful. An example is the ability of pharmacologic doses of gluco-corticoid to suppress inflammation.

A disease due to a disorder of the endocrine system is often called a "HORMONE IMBALANCE", but is technically known as an ENDOCRINOPATHY or ENDOCRINOSIS.

Among the hundreds of endocrine diseases are: Adrenal hyperplasia Diabetes mellitus Hypoglycemia Insulinoma Metabolic bone disease (osteoporosis, rickets and osteomalacia) Pituitary tumors Hyper or hypoparathyroidism Disorders of sex development or intersex disorders Ovarian failure Testicular failure Delayed puberty Menstrual function or fertility disorders (amenorrhea) Goiter , swelling in the thyroid gland due to iodine deficiency. Hyper or hypothyroidism Thyroiditis, is the inflammation of the thyroid gland. Thyroid cancer Tumours of the endocrine glands (Incidentaloma)

The ovaries of sexually-mature females secrete: Estrogens Progesterone.

Estrogens are primarily responsible for the conversion of girls into sexually-mature women, participate in the monthly preparation of the body for a possible pregnancy and participate in pregnancy if it occurs

Estrogens also have non-reproductive effects such as: They antagonize the effects of the parathyroid hormone,

minimizing the loss of calcium from bones and thus helping to keep bones strong.

They promote blood clotting. Estrogen is needed for both sexes for normal bone development.

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Progesterone has many effects in the body (menstrual cycle and pregnancy).

Many menopausal women elect to take a combination of estrogen and progesterone as a hormone replacement therapy (HRT) for:

reduction in the unpleasant symptoms of the menopause a reduction in the loss of calcium from bones and thus a reduction

in osteoporosis and the fractures that accompany it.

Some chemicals that find their way into the environment, such as DDT, DDE and PCBs called ENVIRONMENTAL ESTROGENS because they can bind to the estrogen receptors and mimic (weakly) the effects of the hormone. This may be responsible for harmful effects such as cancer and low sperm counts

Secretion of testosterone increases sharply at puberty and is responsible for the development of the so-called secondary sexual characteristics of men. Testosterone is also essential for the production of sperm.

Steroid hormones can be grouped into five groups by the receptors to which they bind:

6. Glucocorticoids 7. Mineralocorticoids 8. Androgens 9. Estrogens 10.Progestagens

Steroids are lipophilic, low-molecular weight compounds derived from cholesterol that play a number of important physiological roles.

The steroid hormones are synthesized mainly by endocrine glands such as:

The gonads (testis and ovary) The adrenals The fetoplacental unit , during gestation

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It has been recently discovered that, in addition to the endocrine glands, the CNS is also able to form a number of biologically active steroids directly from cholesterol (the so-called "NEUROSTEROIDS").

These neurosteroids, however, are more likely to have "autocrine" or "paracrine" functions rather than true endocrine effects.

Steroid metabolism is therefore important not only for the production of these hormones, but also for the regulation of their cellular and physiological actions.

The parent compound from which all steroids are derived is cholesterol.

As shown before cholesterol is made up of three hexagonal carbon rings (A,B,C) and a pentagonal carbon ring (D) to which a side-chain (carbons 20-27) is attached (at position 17 of the polycyclic hydrocarbon). Two angular methyl groups are also found at position 18 and 19. Removal of part of the side-chain gives rise to C21-compounds of the pregnane series (progestins and corticosteroids).

Total removal produces C19-steroids of the androstane series (including the androgens), whereas loss of the 19-methyl group (usually after conversion of the A-ring to a phenolic structure, hence the term "aromatization") yields the estrane series, to which estrogens belong.

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Steroid hormone biosynthesis: The adrenals produce both androgens and corticosteroids

(mineralo- and glucocorticoids). The ovaries can secrete estrogens and progestins. The testis mainly androgens.

78

A general outline of the major biosynthetic pathways

Examples of some routes of steroid metabolism:Cholesterol can be synthetized in all steroid-producing tissues from acetate, but the main production sites are the liver, the skin and the intestinal mucosa.

79

80

Enzymes involved in steroid biosynthesis: Desmolases (or lyases): these enzymes catalyse reactions which

result in the removal of parts of the original cholesterol side-chain. This requires a cytochrome P-450, molecular oxygen (O2) and nicotinamide dinucleotide phosphate, reduced form (NADPH) as a cofactor.

Hydroxylases: these enzymes are membrane-bound and are present either in the mitochondrial or in the microsomal fraction of the cell. They also require a cytochrome P-450, molecular oxygen and NADPH, as for lyases.

Hydroxysteroid dehydrogenases (oxido-reductases): these enzymes catalyze reversible reactions and depend either on NADP(H) or NAD(H). They are found both in the cell cytosol and in the microsomal fraction.

Aromatase: conversion of the A-ring to a phenolic structure (i.e. with a phenolic HO-group at C-3), a process known as " aromatization ", involves a complex sequence of hydroxylation reactions and loss of the angular C-19 methyl group (10).

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Questions:I. Put circle around the most suitable answer

1. Serum is(a) obtained by centrifuging the blood without clotting(b) obtained by centrifuging the blood after clotting(c) containing all blood cells and platelets(d) containing fibrinogen

2. If the chemical signal acts on the same cell and then responds to, the mechanism called (a) autocrine signaling(b) paracrine signaling(c) endocrine signaling

3. If the Chemical signals diffuse into the area and interact with receptors on nearby cells, the mechanism called (a) autocrine signaling(b) paracrine signaling(c) endocrine signaling

4. If the chemicals are secreted into the blood and carried to the cells they act upon, the mechanism called (a) autocrine signaling(b) paracrine signaling(c) endocrine signaling

5. Hormone secretion can be stimulated or inhibited by:(a) other hormones (b) plasma concentrations of ions or nutrients (c) environmental changes (d) all answers are correct

II. Complete the following statements:

1. The endocrine system consists of several glands secrete hormones directly into the blood rather than into a duct system.

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2. Any chemical to be classified as hormone must be produced by an organ, released in small amounts into the blood and transported to its specific function.

3. Endocrine hormones are secreted directly into the bloodstream while Exocrine hormones are secreted directly into a duct and then either flow into the bloodstream or from cell to cell.

4. Endocrine organs include the pituitary gland, thyroid gland, adrenal gland, ovaries, testes and pancreas.

5. Amine hormones such as nor-epinephrine, epinephrine, and dopamine, are derived from the amino acid tyrosine.

6. Steroid hormones can be grouped into five groups by the receptors to which they bind:

1. Glucocorticoids 2. Mineralocorticoids 3. Androgens4. Estrogens5. Progestagens

III. Draw the structure and name of the missing compounds in the following metabolic pathway.

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STEROID INACTIVATION AND CATABOLISM Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one.

Inactivation can occur at various stages of hormone action.

Peripheral inactivation (e.g. by liver enzymes) is required to ensure steady-state levels of plasma hormones as steroids are more or less continuously secreted into the bloodstream.

Hormone inactivation can also occur in target tissues, after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action.

The main site of peripheral steroid inactivation and catabolism is the liver, but some catabolic activity also occurs in the kidneys.

Inactive hormones are mainly eliminated as urinary (mostly conjugated) metabolites. Usually, steroids are eliminated once they have been inactivated (i.e., they are not " recycled "). This elimination (e.g. as a urinary excretion products) requires conversion to hydrophilic compounds in order to

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ensure their solubility in biological fluids at rather high concentrations.

Depending on the structure of the starting steroid, the following reactions may be involved:

Reduction of a double bond at C-4 and reduction of an oxo (keto) group at C-3 to a secondary alcoholic group.

Reduction of an oxo group at C-20 to a secondary alcoholic group.

Oxidation of a 17ß-hydroxyl group. Further hydroxylations at various positions of

the steroid nucleus (e.g. 7-hydroxylation of 5a-reduced androgens).

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Conjugation (sulphate and/or glucuronide derivatives).

Formation of steroid conjugatesConjugation (formation of hydrophilic molecules) is an important step in steroid catabolism. Most excretory products are in conjugated form.

Two major pathways are used:(a) Formation of glucuronides: This reaction requires uridine diphosphoglucuronic acid (UDPGA) and a glucuronyl transferase. Glucuronic acid is attached to a HO-group on the steroid molecule:

1. Activation of conjugating agent: Uronic acid + UTP to uridine diphosphoglucuronic acid (UDPGA).

Uronic acid + UTP UDPGA2. Active conjugating agent (UDPGA) +

Substrate (steroid)

glucuronyl transferaseSteroid-OH + UDPGA Steroid glucuronide

(b) Formation of sulphates:

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This conversion is catalyzed by sulpho kinases, which occur in the cytosol of liver, testicular, adrenal and fetal tissues. The substrates are steroids with an HO-group and phosphoadenosine-5’-phosphosulphate (PAPS).

This is a three-step reaction which requires Mg++

ions:

Activation of congugatig agent (SO4) to PAPS ATP sulphurylase

(1) SO4-- + ATP Adenosine-5’-phosphosulphate (APS) + pyrophosphate (P-Pi)

ATP kinase

(2) APS + ATP Phosphoadenosine-5’-phosphosulphate (PAPS) Substrate + PAPS ATP sulphokinase

(3) Steroid-OH + PAPS Steroid-O-SO3

-

+ 3’,5’-phosphoadenosine (PAP) + H+

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Amine hormone metabolismEpinephrine (Adrenaline)

Epinephrine (Adrenaline)

Epinephrine is a hormone and neurotransmitter. When produced in the body it increases heart rate, dilates blood vessels.

Epinephrine plays a central role in the short-term stress reaction. It is released from the adrenal glands when danger threatens or in an emergency, hence an Adrenaline rush. Such triggers may be threatening, exciting, or environmental stressor conditions such as high noise levels, or bright light and high ambient temperature.

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Mechanism of action

β-adrenergic receptors

Epinephrine's actions are mediated through adrenergic receptors. Epinephrine is a non-selective agonist of all adrenergic receptors. It activates α1, α2, β1, and β2 receptors to different extents.

Specific functions include:

It binds to α1 receptors of liver cells, which activate inositol-phospholipid signaling pathway, signaling the phosphorylation of glycogen synthase and phosphorylase kinase leading to the latter activating another enzyme—glycogen phosphorylase—which catalyzes

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breakdown of glycogen (glycogenolysis) so as to release glucose to the bloodstream.

Simultaneously protein phosphatase-1 (PP1) is inactivated, as in the active state PP1 would reverse all the previous phosphorylations.

Epinephrine also activates β-adrenergic receptors of the liver and muscle cells, thereby activating the adenylate cyclase signaling pathway, which will in turn increase glycogenolysis.

β2 receptors are found primarily in skeletal muscle blood vessels where they trigger vasodilation. However, α-adrenergic receptors are found in most smooth muscles and epinephrine triggers vasoconstriction in those vessels.

Norepinephrine Synthesis and Release

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Norepinephrine (NE) is the primary neurotransmitter for postganglionic sympathetic adrenergic nerves. It is synthesized inside the nerve axon, stored within vesicles, then released by the nerve when an action potential travels down the nerve. Below are the details for release and synthesis of NE:

1. The amino acid tyrosine is transported into the sympathetic nerve axon.

2. Tyrosine (Tyr) is converted to DOPA by tyrosine hydroxylase (rate-limiting step for NE synthesis).

3. DOPA is converted to dopamine (DA) by DOPA decarboxylase.

4. Dopamine is transported into vesicles then converted to norepinephrine (NE) by dopamine β-hydroxylase (DBH); transport into the vesicle can by blocked by the drug reserpine.

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5. An action potential traveling down the axon depolarizes the membrane and causes calcium to enter the axon.

6. Increased intracellular calcium causes the vesicles to migrate to the axonal membrane and fuse with the membrane, which permits the NE to diffuse out of the vesicle into the extracellular (junctional) space. DBH, and depending on the nerve other secondary neurotransmitters (e.g., ATP), is released along with the NE.

7. The NE binds to the postjunctional receptor and stimulates the effector organ response.

Epinephrine Synthesis and ReleaseEpinephrine is synthesized from norepinephrine within the adrenal medulla, which are small glands associated with the kidneys. Preganglionic fibers sympathetic adrenergic nerves synapse within the adrenals. Activation of these fibers releases acetylcholine, which binds to postjunctional nicotinic receptors in the tissue. This leads to stimulation of NE synthesis within adenomedullary cells, but unlike sympathetic neurons, there is an additional enzyme (phenylethanolamine-N-methyltransferase) that adds a methyl group to the NE molecule to form epinephrine. The epinephrine

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is released into the blood perfusing the glands and carried throughout the body.

Norepinephrine and Epinephrine Removal and Metabolism:The binding of NE to its receptor depends on the concentration of NE in the vicinity of the receptor. If the nerve stops releasing NE, then the NE concentration in the junctional cleft will decrease and NE will leave the receptor. There are several mechanisms by which the norepinephrine is removed from the intercellular (junctional) space and therefore from the postjunctional receptor:

1. Most (~90%) of the NE is transported back into the nerve terminal by a neuronal reuptake transport system. This transporter is blocked by cocaine; therefore, cocaine increases junctional NE concentrations by blocking its reuptake and subsequent metabolism. (This is a major mechanism by which cocaine stimulates cardiac function and raises blood pressure.)

2. Some of the junctional NE diffuses into capillaries and is carried out of the tissue by the circulation. Therefore, high levels of sympathetic activation in the body increase the plasma concentration of NE and its metabolites.

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3. Some of the junctional NE is metabolized within the extracellular space before reaching the capillaries.

4. A small amount of NE (~5%) is taken up by the postjunctional tissue (termed "extraneuronal uptake") and metabolized.

From this point:

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NE (and epinephrine) is metabolized by catechol-O-methytransferase (COMT) and monoamine oxidase (MAO). The final product of these pathways is vanillylmandelic acid (VMA). This final product, along with its precursors normetanephrine and metanephrine, is measured in urine and plasma in

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the diagnosis of pheochromocytoma, which can cause severe hypertension and cardiac arrhythmias.

Acetylcholine Synthesis and MetabolismAcetyl-CoA is synthesized from pyruvate by mitochondria within cholinergic nerves.  This acetyl-CoA combines with choline that is transported into the nerve axon to form acetylcholine (ACh). The enzyme responsible for this is choline acetyltransferase. The newly formed ACh is then transported into vesicles for storage and subsequent release similar to what occurs for NE. After ACh is released, it is rapidly degraded within the synapse by acetylcholineesterase, to form acetate and choline.

Medical Uses:Epinephrine is used as a drug to treat cardiac arrest and other cardiac dysrhythmias توقف القلب

Due to its vasocontriction effects, epinephrine is the drug of choice for treating anaphylaxis رطHHف It is also useful in treating .الحساسية sepsis تعفن . الدم Allergy patients undergoing immunotherapy may receive an epinephrine rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen. It is also used as a bronchodilator for asthma.

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Epinephrine can also be found in some brands of nasal spray. Its use in this form is to open air passages.

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Epinephrine is synthesized from norepinephrine in a synthetic pathway shared by all catecholamines, including L-dopa, dopamine, and epinephrine.

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Epinephrine is synthesized via methylation of the primary distal amine of norepinephrine by phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons and cells of the adrenal medulla (so-called chromaffin cells). PNMT is only found in the cytosol of cells of adrenal medullary cells. PNMT uses S -adenosylmethionine (SAMe) as a cofactor to donate the methyl group to norepinephrine, creating epinephrine.

For norepinephrine to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized epinephrine from the cytosol back into chromaffin granules in preparation for release.

RegulationEpinephrine synthesis is solely under the control of the Central Nervous System (CNS). Several levels of regulation dominate epinephrine synthesis.

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of epinephrine precursors by enhancing the activity of enzymes involved in catecholamine

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synthesis. The specific enzymes are tyrosine hydroxylase in the synthesis of dopa and enzyme dopamine-β-hydroxylase in the synthesis of norepinephrine.

Calcium triggers the release of epinephrine (and norepinephrine) into the bloodstream.

Dopamine

3,4-dihydroxyphenethylamine

Dopamine is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates.

In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D1, D2, D3, D4, and D5, and their variants.

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Biosynthesis of dopamine

As a member of the catecholamine family, dopamine is a precursor to norepinephrine (noradrenaline) and then epinephrine (adrenaline)

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in the biosynthetic pathways for these neurotransmitters.

Dopamine is biosynthesized in the body (mainly by nervous tissue and the medulla of the adrenal glands) first by the hydroxylation of the amino acid L-tyrosine to L-DOPA via the enzyme tyrosine 3-monooxygenase, also known as tyrosine hydroxylase, and then by the decarboxylation of L-DOPA by aromatic L-amino acid decarboxylase (which is often referred to as dopa decarboxylase). In some neurons, dopamine is further processed into norepinephrine by dopamine beta-hydroxylase.

In neurons, dopamine is packaged after synthesis into vesicles, which are then released into the synapse in response to a presynaptic action potential.

Therapeutic use:Dopamine can be supplied as a medication that acts on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, because dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson's disease and dopa-responsive dystonia, L-DOPA,

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which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.

Peptide hormone metabolismInsulin metabolism

Insulin is a peptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island".

Insulin has extensive effects on metabolism and other body functions. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and

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muscle, and stopping use of fat as an energy source.

When insulin is absent (or low), glucose is not taken up by body cells, and the body begins to use fat as an energy source, for example, by transfer of lipids from adipose tissue to the liver for mobilization as an energy source.

When control of insulin levels fails, diabetes mellitus will result. 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 the hormone is no longer produced internally.

Patients with Type 2 diabetes mellitus are insulin resistant, and because of such resistance, may suffer from a relative insulin deficiency. Some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately.

Protein structure of insulin:Within vertebrates, the similarity of insulins is extremely close. Bovine insulin differs from human

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in only three amino acid residues, and pig insulin in one. Even insulin from some species of fish is similar enough to human to be clinically effective in humans.

Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is an inactive form with long-term stability which serves as a way to keep the highly reactive insulin protected, yet readily available.

The hexamer-monomer conversion is one of the central aspects of insulin formulations for injection. The hexamer is far more stable than the monomer, which is desirable for practical reasons, however the monomer is a much faster reacting drug because diffusion rate is inversely related to particle size. A fast reacting drug means that insulin injections do not have to precede mealtimes by hours, which in turn gives diabetics more flexibility in their daily schedule.

Synthesis, physiological effects, and degradation of insulin:

Synthesis:

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Insulin is produced in the pancreas and released when any of the several stimuli is detected. The stimuli include ingested protein and glucose in the blood produced from digested food. Carbohydrate produces glucose, although not all types of carbohydrate produce glucose and thereby increase blood glucose levels. In target cells, they initiate a signal transduction, which has the effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the response.

In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans. One million 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 (ie, C-peptide), from the C-

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and N- terminal ends of proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds/disulphide bonds.

It has been shown that insulin and its related proteins, are also produced inside the brain and that reduced levels of these proteins are linked to Alzheimer's disease.

Release:Beta cells in the islets of Langerhans release insulin in two phases. The first phase insulin release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles that are triggered independently of sugar.

The description of first phase release is as follows:

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Glucose enters the beta cells through the glucose transporter GLUT2

Glucose goes into glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation

Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K+) close and the cell membrane depolarizes

On depolarization, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells

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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 synthesized insulin, which has been stored in secretory vesicles

This is the main mechanism for release of insulin. In addition some insulin release takes place generally with food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signaling mechanisms controlling these linkages are not fully understood.

Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine.

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Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase.

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. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia.

Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.

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Physiological effects

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).

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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.

Increase of DNA replication and protein synthesis via control of amino acid uptake.

Modification of the activity of numerous enzymes.

DegradationOnce an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment, or it may be degraded by the cell.

Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that an insulin molecule produced endogenously by the pancreatic beta cells is degraded within approximately one hour after its initial release into circulation (insulin half-life ~ 4-6 minutes).

Diseases and syndromes

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There are several conditions in which insulin disturbance is pathologic:

Diabetes mellitus – general term referring to all states characterized by hyperglycemia.

Insulinoma - a tumor of pancreatic beta cells producing excess of insulin or reactive hypoglycemia.

Metabolic syndrome – leading to hypertension, obesity منةHHHHالس , Type 2 diabetes, and cardiovascular disease (CVD) develop.

Polycystic ovary syndrome – a complex syndrome in women in the reproductive years.

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Leptin hormoneLeptin is a 16,000 Da protein hormone with important effects in regulating body weight, metabolism and reproductive function. It plays also a key role in regulating energy intake and energy expenditure. It is one of the most important adipose derived hormones.

Leptin is expressed predominantly by adipocytes, which fits with the idea that body weight is sensed as the total mass of fat in the body.

Smaller amounts of leptin are also secreted by cells in the epithelium of the stomach and in the placenta.

Leptin receptors are highly expressed in areas of the hypothalamus known to be important in regulating body weight, as well as in T lymphocytes and vascular endothelial cells.

Physiologic Effects of Leptin:In addition to being a biomarker for body fat, serum leptin levels also reflect individual energy balance.

Several studies have shown that fasting or following a very low calorie diet lowers leptin levels. It might be that on short term leptin is an

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indicator of energy balance. This system is more sensitive to starvation than to overfeeding. Leptin levels do not rise extensively after overfeeding. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake.

Leptin appears to result from a combination of at least two fundamental effects:

Decreased hunger and food consumption, mediated at least in part by inhibition of neuropeptide Y synthesis. Neuropeptide Y is a very potent stimulator of feeding behavior.

Increased energy expenditure measured ,انفاق as increased oxygen consumption, higher body temperature and loss of adipose tissue mass.

Reproductive Function It has long been known that starvation adversely affect reproductive function. For example, very low body fat in human females is often associated with cessation (stop) of menstrual cycles, and similar effects are seen in starving or nutritionally-deprived animals. Also, the onset of puberty is known to correlate with body condition as well as age.

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Leptin concentrations are low in people and animals with low body fat, and leptin appears to be a significant regulator of reproductive function. These effects are probably due in part to the ability of leptin to enhance secretion of gonadotropin-releasing hormone, and thus luteinizing and follicle-stimulating hormones from the anterior pituitary.

SynthesisIn addition to white adipose tissue—the major source of leptin—it can also be produced by brown adipose tissue, placenta, ovaries, skeletal muscle, stomach, mammary epithelial cells, bone marrow, pituitary and liver.

Control of Leptin Synthesis and SecretionThe amount of leptin expressed by adipocytes is well correlated with the lipid content of the cells. Once synthesized, leptin is secreted through a constitutive pathway and not stored in the cell.

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BLOOD BIOCHEMISTRYBlood carries hormones and disease-fighting substances. Blood picks up oxygen from the lungs and nutrients from the gastrointestinal tract and carries them to cells throughout the body for metabolism. It picks up carbon dioxide and other wastes from those cells and transports them to the lungs and excretory organs.

Blood consists of plasma, red and white cells (erythrocytes and leukocytes), and platelets (thrombocytes).

Blood disorders include: Polycythemia (abnormal increase in the

number of circulating red blood cells). Anemia. Leukemia

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Hemophilia نزيف وراثي

Technically, blood is a transport liquid pumped by the heart to all parts of the body, after which it is returned to the heart to repeat the process.

Blood is both a tissue and a fluid. It is a tissue because it is a collection of similar specialized cells that serve particular functions. These cells are suspended in a liquid matrix (plasma), which makes the blood as fluid.

If blood flow ceases, death will occur within minutes because of the effects of an unfavorable environment on highly susceptible cells.

The constancy of the composition of the blood is made possible by the circulation, which conveys blood through the organs that regulate the concentrations of its components.

In the lungs, blood acquires oxygen and releases carbon dioxide transported from the tissues.

Nutrient substances derived from food reach the bloodstream after absorption by the gastrointestinal tract.

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Glands of the endocrine system release their secretions into the blood, which transports these hormones to the tissues in which they exert their effects.

Many substances are recycled through the blood; for example, iron released during the destruction of old red cells is conveyed by the plasma to sites of new red cell production where it is reused.

Each of the numerous components of the blood is kept within appropriate concentration limits by an effective regulatory mechanism. In many instances, feedback control systems are operative; thus, a declining level of blood sugar (glucose) leads to accelerated release of glucose into the blood so that a potentially hazardous depletion of glucose does not occur.

The red pigment hemoglobin, which contains iron, is found in all vertebrates including humans, hemoglobin is contained exclusively within the red cells (erythrocytes). The pigment concentrations required would cause the blood to be so viscous as to impede circulation.

Hemoglobin

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It is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates.In mammals, the protein makes up about 97% of the red blood cell's dry content, and around 35% of the total content (including water).

Hemoglobin transports oxygen from the lungs to the rest of the body (i.e. the tissues) where it releases the oxygen for cell use. It also has a variety of other roles of gas transport and effect-modulation which vary from species to species, and are quite diverse in some invertebrates. For example, hemoglobin transports CO2 back from the tissues to the lungs.Hemoglobin has an oxygen binding capacity of between 1.36 and 1.37 ml O2 per gram of hemoglobin, which increases the total blood oxygen capacity seventyfold.

SynthesisHemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol. Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow.

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At this point, the nucleus is lost in mammalian red blood cells. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).

Structure

Heme group

Hemoglobin exhibits characteristics of both the tertiary and quaternary structures of proteins. Most of the amino acids in hemoglobin form alpha helices, connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the

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molecule, folding each polypeptide chain into a specific shape.

Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.

In most humans, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement, so called because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin. This folding pattern contains a pocket which strongly binds the heme group.

A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. A porphyrin ring consists of four pyrrole molecules cyclically linked together with the iron ion bound in the centre.

That set

The iron ion, which is the site of oxygen binding (i.e. transporting the oxygen and CO2 in the blood), coordinates with the four nitrogens in the center of

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the ring, which all lie in one plane. The iron is bound strongly to the globular protein via the imidazole ring of the F8 histidine residue below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond, completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

The iron ion may either be in the Fe2+ or Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen. In binding, oxygen temporarily oxidizes (Fe2+) to (Fe3+), so iron must exist in the +2 oxidation state to bind oxygen.

The enzyme methemoglobin reductase reactivates hemoglobin found in the inactive (Fe3+) state by reducing the iron center.

Generally speaking, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).

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Oxyhemoglobin is formed during respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized in aerobic glycolysis and in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH. Deoxyhemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This accounts for hemoglobin's red colour and deoxyhemoglobin's blue colour. This difference is used for measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter.

Degradation in vertebrate animalsWhen red cells reach the end of their life due to aging or defects, they are broken down, the

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hemoglobin molecule is broken up and the iron gets recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bile by the liver.

This process also produces one molecule of carbon monoxide for every molecule of heme degraded. This is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air.

The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage.

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Role of blood in diseaseIn sickle cell hemoglobin (HbS), GLUTAMIC ACID is mutated to VALINE.

This change allows the deoxygenated form of the hemoglobin to stick to each other.

Hemoglobin deficiency can be caused by either one of the followings:

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1. decreased amount of hemoglobin molecules as in anemia.

2. decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen.

Hemoglobinopathies (genetic defects resulting in

abnormal structure of the hemoglobin molecule) may cause both of above.

In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity.

Hemoglobin deficiency is generally strictly distinguished from hypoxemia (defined as decreased partial pressure of oxygen in blood).

Both of Hemoglobin deficiency and hypoxemia are causes hypoxia (insufficient oxygen supply to tissues).

Other common causes of low hemoglobin include: loss of blood nutritional deficiency bone marrow problems chemotherapy kidney failure abnormal hemoglobin (such as that of sickle

cell disease)

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High hemoglobin levels may be caused by: exposure to high altitudes smoking dehydration tumors

The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO2, causing an altered oxygen-hemoglobin dissociation curve. However, it can also be pathologically altered in e.g. carbon monoxide poisoning.

Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia.

Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are HYPOCHROMIC (lacking the red hemoglobin pigment) and MICROCYTIC (smaller than normal).

In hemolysis (accelerated breakdown of red blood cells), associated jaundice شعور بالضيق is caused by

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the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations are referred to merely as hemoglobin variants.

There is a group of genetic disorders, known as the PORPHYRIAS that are characterized by errors in metabolic pathways of heme synthesis.

GLYCOSYLATED HEMOGLOBIN is the form of hemoglobin to which glucose is bound. Glucose stays attached to the hemoglobin for the life of the red blood cells, which is approximately 120 days. The levels of glycosylated hemoglobin are tested to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM).

Poor control of T2DM results in high levels of glycosylated hemoglobin in the red blood cells.

The normal reference range is approximately 4 %–5.9 %. Though difficult to obtain, values less than 7 % are recommended for people with T2DM.

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Levels greater than 9 % are associated with poor control of the glycosylated hemoglobin and levels greater than 12 % are associated with very poor control.

Diabetics who keep their glycosylated hemoglobin levels close to 7 % have a much better chance of avoiding the complications that can sometimes accompany diabetes (than those whose levels are 8 % or higher).

URINE BIOCHEMISTRYUrine is a liquid waste product of the body secreted by the kidneys by a process of filtration from blood called urination.

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Cellular metabolism generates many waste compounds, many rich in nitrogen, that require elimination from the bloodstream.

This waste is eventually expelled from the body in a process known as MICTURITION, the primary method for excreting water-soluble chemicals from the body. These chemicals can be detected and analyzed by urinalysis.

Renal physiologySoluble wastes are excreted through urination process. The kidneys extract the soluble wastes from the bloodstream, as well as excess water, sugars, and a variety of other compounds.

The composition of urine is adjusted in the process of REABSORPTION whereby certain solutes, such as glucose, are reabsorbed back into the blood stream via carrier molecules. The remaining fluid contains high concentrations of urea and other substances, including toxins.

Urine is produced by a process of 1. Filtration 2. Reabsorption 3. Tubular secretion

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COMPOSITIONUrine is an aqueous solution of approximately

95% water 5% metabolic wastes such as

1. urea 2. dissolved inorganic salts 3. organic compounds, including proteins,

hormones, and a wide range of metabolites.

Fluid and materials being filtered by the kidneys, destined (intended) to become urine, come from the blood or interstitial fluid.

Except in cases of kidney or urinary tract infection, urine is nearly odorless. Subsequent to elimination from the body, urine can acquire strong odors due to bacterial action.

Urea structure

Ammonia is produced by breakdown of urea. Some diseases alter the quantity and consistency of the urine, such as sugar as a consequence of diabetes.

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CharacteristicsThe typical color of urine is caused by the pigment UROCHROME as well as the degradation products of BILIRUBIN and UROBILIN. It can range from clear to a dark amber, depending mostly upon the level of hydration of the body, among other factors.

Unusual color Colorless- indicates over-hydration, which is

usually considered much healthier than dehydration. Yellowing/light orange may be caused by removal of excess B vitamins from the bloodstream.

Certain medications such as rifampin and pyridium can cause orange urine.

Bloody urine is termed HEMATURIA, potentially a sign of a bladder infection.

Consumption of beets can cause urine to have a pinkish tint (color); the condition is harmless and temporary.

Dark orange to brown urine can be a symptom of jaundice, rhabdomyolysis, or Gilbert's syndrome.

Black or dark-colored urine is referred to as melanuria and may be caused by a melanoma.

Reddish or brown urine may be caused by porphyria. Again, the consumption of beets can

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cause the urine to have a harmless, temporary pink or reddish tint.

Greenish color is usually a consequence of consuming asparagus.

Fluorescent yellow / greenish urine may be caused by dietary supplemental vitamins, especially the B vitamins.

Dark yellow urine is usually indicative of dehydration.

OdorThe smell of urine can be affected by the consumption of food. Eating asparagus is known to produce a strong odour in human urine. This is due to the body's breakdown of asparagusic acid. Other foods that contribute to odor include curry, alcohol, coffee, turkey and onion.

TurbidityTurbid urine may be a symptom of a bacterial infection, but can also be due to crystallization of salts such as calcium phosphate.

pHThe pH of urine is close to neutral (7) but can normally vary between 6.5 and 7.4

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In persons with HYPER URICOS URIA, acidic urine can contribute to the formation of stones of uric acid in the kidneys or bladder.

VolumeThe amount of urine produced depends on numerous factors including state of hydration, activities, environmental factors, size, and health. In adult humans the average production is about 1 - 2 L/day.

Producing too much or too little urine needs medical attention: Polyuria is a condition of excessive production of urine (> 2.5 L/day), in contrast to oliguria where < 400 mL are produced per day, or anuria with a production of < 100 mL per day.

Chemical synapseChemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological

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computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

At a chemical synapse, one neuron releases a neurotransmitter into a small space (the synapse) that is adjacent to another neuron. Neurotransmitters must then be cleared out of the synapse efficiently so that the synapse can be ready to function again as soon as possible.

The adult human brain is estimated to contain from 1014 to 5 × 1014 (100-500 trillion) synapses. Every cubic millimeter of cerebral cortex contains roughly a billion of them.

The word "synapse" comes from "synaptein", which Sir Charles Scott Sherrington and colleagues coined from the Greek "syn-" ("together") and "haptein" ("to clasp"). Chemical synapses are not the only type of biological synapse: electrical and immunological synapses also exist. Without a qualifier, however, "synapse" commonly means chemical synapse.

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Illustration of the major elements in chemical synaptic transmission. An electrochemical wave called an action potential travels along the axon of a neuron. When the wave reaches a synapse, it provokes release of a puff of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse.

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StructureSynapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are some types that make far fewer. Most synapses connect axons to dendrites, but there are also other types of connections, including axon-to-cell-body, axon-to-axon, and dendrite-to-dendrite.

Synapses are generally too small to be recognizable using a light microscope except as points where the membranes of two cells appear to touch, but their cellular elements can be visualized clearly using an electron microscope.

Chemical synapses pass information directionally from a pre-synaptic cell to a post-synaptic cell and are therefore asymmetric in structure and function. The pre-synaptic terminal, or synaptic bouton, is a specialized area within the axon of the pre-synaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles. Synaptic vesicles are docked at the pre-synaptic plasma membrane at regions called active zones (AZ)

Immediately opposite is a region of the postsynaptic cell containing neurotransmitter

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receptors; for synapses between two neurons the postsynaptic region may be found on the dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called the post-synaptic density (PSD).

Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors and modulating the activity of these receptors. The receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines.

Between the pre- and postsynaptic cells is a gap about 20 nm wide called the synaptic cleft. The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly. The membranes of the two adjacent cells are held together by cell adhesion proteins.

Signaling in chemical synapsesHere is a summary of the sequence of events that take place in synaptic transmission from a pre-synaptic neuron to a post-synaptic cell. Each step is explained in more detail below. Note that with the exception of the final step, the entire process may run only a few tenths of a millisecond, in the fastest synapses.

1. The process begins with a wave of electrochemical excitation called an action

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potential traveling along the membrane of the pre-synaptic cell, until it reaches the synapse.

2. The electrical depolarization of the membrane at the synapse causes channels to open that are permeable to calcium ions.

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3. Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior.

4. The high calcium concentration activates a set of calcium-sensitive proteins attached to vesicles that contain a neurotransmitter chemical.

5. These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and post-synaptic cells.

6. The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it binds to chemical receptor molecules located on the membrane of the postsynaptic cell.

7. The binding of neurotransmitter causes the receptor molecule to be activated in some way. Several types of activation are possible, as described in more detail below. In any case, this is the key step by which the synaptic process affects the behavior of the postsynaptic cell.

8. Due to thermal shaking, neurotransmitter molecules eventually break loose from the receptors and drift away.

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9. The neurotransmitter is either reabsorbed by the presynaptic cell, and then repackaged for future release, or else it is broken down metabolically.

Neurotransmitter release

The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action potential) and occurs through an unusually rapid process of cellular secretion, also known as exocytosis: Within the presynaptic nerve terminal, vesicles containing neurotransmitter sit "docked" and ready at the synaptic membrane. The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current). Calcium ions then trigger a biochemical cascade which results in vesicles fusing with the pre-synaptic membrane and releasing their contents to the synaptic cleft within 180µsec of calcium entry. Vesicle fusion is driven by the action of a set of proteins in the pre-synaptic terminal known as SNAREs.

As calcium ions enter into the pre-synaptic neuron, they bind with the proteins found within the membranes of the synaptic vesicles that allow the

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vesicles to "dock." Triggered by the binding of the calcium ions, the synaptic vesicle proteins begin to move apart, resulting in the creation of a fusion pore. The presence of the pore allows for the release of neurotransmitter into the synapse.

The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles.

Receptor bindingReceptors on the opposite side of the synaptic gap bind neurotransmitter molecules and respond by opening nearby ion channels in the postsynaptic cell membrane, causing ions to rush in or out and changing the local transmembrane potential of the cell. The resulting change in voltage is called a postsynaptic potential.

In general, the result is excitatory, in the case of depolarizing currents, or inhibitory in the case of hyperpolarizing currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the postsynaptic current display(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse.

Termination

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After a neurotransmitter molecule binds to a receptor molecule, it does not stay bound forever: sooner or later it is shaken loose by random temperature-related jiggling. Once the neurotransmitter breaks loose, it can either drift away, or bind again to another receptor molecule. The pool of neurotransmitter molecules undergoing this binding-loosening cycle steadily diminishes, however. Neurotransmitter molecules are typically removed in one of two ways, depending on the type of synapse: either they are taken up by the presynaptic cell (and then processed for re-release during a later action potential), or else they are broken down by special enzymes. The time course of these "clearing" processes varies greatly for different types of synapses, ranging from a few tenths of a millisecond for the fastest, to several seconds for the slowest.

DesensitizationDesensitization of the postsynaptic receptors is a decrease in response to the same neurotransmitter stimulus. It means that the strength of a synapse may in effect diminish as a train of action potentials arrive in rapid succession--a phenomenon that gives rise to the so-called frequency dependence of synapses. The nervous system exploits this property for computational purposes, and can tune

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its synapses through such means as phosphorylation of the proteins involved.

Effects of drugsOne of the most important features of chemical synapses is that they are the site of action for the majority of psychoactive drugs. Synapses are affected by drugs such as curare, strychnine, cocaine, morphine, alcohol, LSD, and countless others. These drugs have different effects on synaptic function, and often are restricted to synapses that use a specific neurotransmitter. For example, curare is a poison which stops acetylcholine from depolarising the post-synaptic membrane, causing paralysis. Strychnine blocks the inhibitory effects of the neurotransmitter glycine, which causes the body to pick up and react to weaker and previously ignored stimuli, resulting in uncontrollable muscle contractions. Morphine acts on synapses that use endorphin neurotransmitters, and alcohol increases the inhibitory effects of the neurotransmitter GABA. LSD interferes with synapses that use the neurotransmitter serotonin to cause hallucination. Cocaine blocks reuptake of dopamine and therefore increases its effects.

Neurotransmitters

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They are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse.

Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation.

Identifying neurotransmittersChemicals can be classified as neurotransmitters if they meet the following conditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.

The chemical is present in the presynaptic element.

It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron.

There are postsynaptic receptors and the chemical is able to bind to them.

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A biochemical mechanism for inactivation is present.

Types of neurotransmittersThere are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some purposes.

Major neurotransmitters1. Amino acids: glutamate, aspartate, serine,

-aminobutyric acid (GABA), glycine. 2. Monoamines: dopamine (DA), norepinephrine

(noradrenaline; NE, NA), epinephrine (adrenaline), serotonin (SE, 5-HT), melatonin

3. Others: acetylcholine (ACh), adenosine, anandamide, histamine, nitric oxide, etc.

Not all neurotransmitters are equally important. By far the most prevalent transmitter is glutamate, which is used at well over 90% of the synapses in the human brain. The next most prevalent is GABA, which is used at more than 90% of the synapses that don't use glutamate.

Note, however, that even though other transmitters are used in far fewer synapses, they may be very important functionally: the great majority of

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psychoactive drugs exert their effects by altering the actions of some neurotransmitter system, and the great majority of these act through transmitters other than glutamate or GABA. Addictive drugs such as cocaine, amphetamine, and heroin, for example, exert their effects primarily on the dopamine system.

Excitatory and inhibitorySome neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a neurotransmitter is to activate one or more types of receptors.

The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential.

For other neurotransmitters (such as GABA), the most important receptors all have inhibitory effects. There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate

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complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently.

ActionsAs explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to.

Degradation and eliminationNeurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. For example, acetylcholine, (ACh) (an excitatory neurotransmitter), is broken down by acetylcholinesterase (AChE).

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Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be the target of the body's own regulatory system or recreational drugs.

AcetylcholineAcetylcholine (ACh) is a simple molecule synthesized from choline and acetyl-CoA through the action of choline acetyltransferase.

Neurons that synthesize and release ACh are termed cholinergic neurons. When an action potential reaches the terminal button of a presynaptic neuron a voltage-gated calcium channel is opened.

The influx of calcium ions, Ca2+, stimulates the exocytosis of presynaptic vesicles containing ACh, which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase.

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The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid.

Two main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool alkaloid, muscarine, and to nicotine, respectively: the muscarinic receptors and the nicotinic receptors.

Both receptor classes are abundant in the human brain. Nicotinic receptors are further divided into those found at neuromuscular junctions and those found at neuronal synapses. The activation of ACh receptors by the binding of ACh leads to an influx of Na+ into the cell and an efflux of K+, resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential.

Cholinergic Agonists and AntagonistsNumerous compounds have been identified that act as either agonists or antagonists of cholinergic neurons. The principal action of cholinergic agonists is the excitation or inhibition of autonomic effector cells that are innervated by postganglionic parasympathetic neurons and as such are refered to as parasympathomimetic agents. The cholinergic agonists include choline esters (such as ACh itself)

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as well as protein- or alkaloid-based compounds. Several naturally occurring compounds have been shown to affect cholinergic nerons, either positively or negatively.

The responses of cholinergic neurons can also be enhanced by administration of cholinesterase (ChE) inhibitors. ChE inhibitors have been used as components of nerve gases but also have significant medical application in the treatment of disorders such as glaucoma and myasthenia gravis as well as in terminating the effects of neuromuscular blocking agents such as atropine.

CatecholaminesThe principal catecholamines are norepinephrine, epinephrine and dopamine. These compounds are formed from phenylalanine and tyrosine.

Tyrosine is produced in the liver from phenylalanine through the action of phenylalanine hydroxylase. The tyrosine is then transported to catecholamine-secreting neurons where a series of reactions convert it to dopamine, to norepinephrine and finally to epinephrine (see Specialized Products of Amino Acids).

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Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity. The excitatory effects are exerted upon smooth muscle cells of the vessels that supply blood to the skin and mucous membranes.

Cardiac function is also subject to excitatory effects, which lead to an increase in heart rate and in the force of contraction. Inhibitory effects, by contrast, are exerted upon smooth muscle cells in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle.

In addition to their effects as neurotransmitters, norepinephrine and epinephrine can influence the rate of metabolism. This influence works both by modulating endocrine function such as insulin secretion and by increasing the rate of glycogenolysis and fatty acid mobilization.

The catecholamines bind to two different classes of receptors termed the - and -adrenergic receptors. The catecholamines therefore are also known as adrenergic neurotransmitters; neurons that secrete them are adrenergic neurons.

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Norepinephrine-secreting neurons are noradrenergic. The adrenergic receptors are classical serpentine receptors that couple to intracellular G-proteins. Some of the norepinephrine released from presynaptic noradrenergic neurons recycled in the presynaptic neuron by a reuptake mechanism.

Catecholamine CatabolismEpinephrine and norepinephrine are catabolized to inactive compounds through the sequential actions of catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO).

Compounds that inhibit the action of MAO have been shown to have beneficial effects in the treatment of clinical depression, even when tricyclic antidepressants are ineffective.

The utility of MAO inhibitors was discovered serendipitously when patients treated for tuberculosis with isoniazid showed signs of an improvement in mood; isoniazid was subsequently found to work by inhibiting MAO.

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SerotoninSerotonin (5-hydroxytryptamine, 5HT) is formed by the hydroxylation and decarboxylation of tryptophan (see Specialized Products of Amino Acids). The greatest concentration of 5HT (90%) is found in the enterochromaffin cells of the gastrointestinal tract. Most of the remainder of the body's 5HT is found in platelets and the CNS.

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The effects of 5HT are felt most prominently in the cardiovascular system, with additional effects in the respiratory system and the intestines. Vasoconstriction is a classic response to the administration of 5HT.

Neurons that secrete 5HT are termed serotonergic. Following the release of 5HT, a portion is taken back up by the presynaptic serotonergic neuron in a manner similar to that of the reuptake of norepinephrine.

GABASeveral amino acids have distinct excitatory or inhibitory effects upon the nervous system. The amino acid derivative, -aminobutyrate, also called 4-aminobutyrate, (GABA) is a well-known inhibitor of presynaptic transmission in the CNS, and also in the retina. The formation of GABA occurs by the decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD). GAD is present in many nerve endings of the brain as well as in the -cells of the pancreas. Neurons that secrete GABA are termed GABAergic.

GABA exerts its effects by binding to two distinct receptors, GABA-A and GABA-B. The GABA-A receptors form a Cl- channel. The binding of GABA

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to GABA-A receptors increases the Cl- conductance of presynaptic neurons. The anxiolytic drugs of the benzodiazepine family exert their soothing effects by potentiating the responses of GABA-A receptors to GABA binding. The GABA-B receptors are coupled to an intracellular G-protein and act by increasing conductance of an associated K+ channel.

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