The endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

Most hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

Principal functions of the endocrine systemMaintenance of the internal environment in the body (maintaining the optimum biochemical environment).Integration and regulation of growth and development.Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn.

Classic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

Endocrine action: the hormone is distributed in blood and binds to distant target cells. Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood. Autocrine action: the hormone acts on the same cell that produced it.

Major hormones and systemsTop down organization of endocrine system.Hypothalamus produces releasing factors that stimulate production of anterior pituitary hormone which act on peripheral endocrine gland to stimulate release of third hormoneSpecific examples to followPosterior pituitary hormones are synthesized in neuronal cell bodies in the hypothalamus and are released via synapses in posterior pituitary. Oxytocin and antidiuretic hormone (ADH)

Types of hormonesHormones are categorized into four structural groups, with members of each group having many properties in common: Peptides and proteins Amino acid derivatives Steroids Fatty acid derivatives - Eicosanoids

Peptide/protein hormonesRange from 3 amino acids to hundreds of amino acids in size. Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone. Peptide/protein hormones are water soluble.Comprise the largest number of hormones perhaps in thousands

Peptide/protein hormonesAre encoded by a specific gene which is transcribed into mRNA and translated into a protein precursor called a preprohormonePreprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation)Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormoneProhormone is processed into active hormone and packaged into secretory vessicles

Peptide/protein hormonesSecretory vesicles move to plasma membrane where they await a signal. Then they are exocytosed and secreted into blood stream In some cases the prohormone is secreted and converted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung

Amine hormonesThere are two groups of hormones derived from the amino acid tyrosineThyroid hormones and Catecholamines

Thyroid HormoneThyroid hormones are basically a "double" tyrosine with the critical incorporation of 3 or 4 iodine atoms. Thyroid hormone is produced by the thyroid gland and is lipid solubleThyroid hormones are produced by modification of a tyrosine residue contained in thyroglobulin, post-translationally modified to bind iodine, then proteolytically cleaved and released as T4 and T3. T3 and T4 then bind to thyroxin binding globulin for transport in the blood

Catecholamine hormonesCatecholamines are both neurohormones and neurotransmitters. These include epinephrine, and norepinephrine Epinephrine and norepinephrine are produced by the adrenal medulla both are water solubleSecreted like peptide hormones

Amine HormonesTwo other amino acids are used for synthesis of hormones: Tryptophan is the precursor to serotonin and the pineal hormone melatonin Glutamic acid is converted to histamine

Steroid hormonesAll steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it.All steroid hormones are lipid soluble

Types of steroid hormonesGlucocorticoids; cortisol is the major representative in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

Steroid hormonesAre not packaged, but synthesized and immediately releasedAre all derived from the same parent compound: CholesterolEnzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ERSteroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells

Steroid hormonesSteroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins. Corticosteroid binding globulin carries cortisolSex steroid binding globulin carries testosterone and estradiolIn some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins. Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated.

cholesterolExtracellular lipoproteinCholesterol poolLHATPcAMPPKA+PregnenoloneProgesteroneAndrostenedioneTESTOSTERONE3bHSDP450c1717bHSDacetate

1,25-Dihydroxy Vitamin D31,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid solubleNot really a vitamin as it can be synthesized de novoActs as a true hormone

Fatty Acid Derivatives - EicosanoidsArachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell. These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds.

Fatty Acid Derivatives - Eicosanoids Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids. The principal groups of hormones of this class are prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Regulation of hormone secretionSensing and signaling: a biological need is sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are: receipt of stimulus synthesis and secretion of hormone delivery of hormone to target cell evoking target cell response degradation of hormone

The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial.

The concentration of hormone as seen by target cells is determined by three factors: Rate of productionRate of deliveryRate of degradation and elimination

Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits, as described below in more detail.

Rate of delivery: An example of this effect is blood flow to a target organ or group of target cells - high blood flow delivers more hormone than low blood flow.

Rate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes. Shutting off secretion of a hormone that has a very short half-life causes circulating hormone concentration to plummet, but if a hormone's biological half-life is long, effective concentrations persist for some time after secretion ceases.

Feedback loops are used extensively to regulate secretion of hormones in the hypothalamic-pituitary axis. An important example of a negative feedback loop is seen in control of thyroid hormone secretion

Neural controlNeural input to hypothalamus stimulates synthesis and secretion of releasing factors which stimulate pituitary hormone production and release

Chronotropic controlEndogenous neuronal rhythmicityDiurnal rhythms, circadian rhythms (growth hormone and cortisol), Sleep-wake cycle; seasonal rhythm

Episodic secretion of hormonesResponse-stimulus coupling enables the endocrine system to remain responsive to physiological demands Secretory episodes occur with different periodicity Pulses can be as frequent as every 5-10 minutes

Episodic secretion of hormonesThe most prominent episodes of release occur with a frequency of about one hourreferred to as circhoral An episode of release longer than an hour, but less than 24 hours, the rhythm is referred to as ultradian If the periodicity is approximately 24 hours, the rhythm is referred to as circadian usually referred to as diurnal because the increase in secretory activity happens at a defined period of the day.

Feedback controlNegative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretionPositive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation

Substrate-hormone controlGlucose and insulin: as glucose increases it stimulates the pancreas to secrete insulin

Hormone-Receptor interactionsDefinition: a protein that binds a ligand with high affinity and low capacity. This binding must be saturuable. A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action.

Agonist vs. AntagonistAgonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potentlyAntagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signaling events

Hormone-receptor interactionsHormone--receptor interaction is defined by an equilibrium constant called the Kd, or dissociation constant.The interaction is reversible and how easily the hormone is displaced from the receptor is a quantitation of its affinity.Hormone receptor interactions are very specific and the Kd ranges from 10-9 to 10-12 Molar

Spare receptorsIn most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell. Examples: insulin stimulates maximum glucose oxidation in adipocytes with only 2-3% of receptors boundLH stimulates maximum testosterone production in Leydig cells when only 1% of receptors are bound

Spare ReceptorsMaximum response with 2-3% receptor occupancy97% of receptors are spareMaximum biological response is achieved when all of the receptors are occupied on an average of

Classes of hormones The hormones fall into two general classes based on their solubility in water. The water soluble hormones are the catecholamines (epinephrine and norepinephrine) and peptide/protein hormones. The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

Types of receptorsReceptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell. Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell

Second messenger systemsReceptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell

Second messengers for cell-surface receptorsSecond messenger systems include: Adenylate cyclase which catalyzes the conversion of ATP to cyclic AMP; Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides); Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

Second messenger systemsEach of these second messenger systems activates a specific protein kinase enzyme. These include cyclic nucleotide-dependent protein kinases Calcium/calmodulin-dependent protein kinase, and protein kinase C which depends on diacyl glycerol binding for activation. Protein kinase C activity is further increased by calcium which is released by the action of inositol phosphates.

Second messenger systemsThe generation of second messengers and activation of specific protein kinases results in changes in the activity of the target cell which characterizes the response that the hormone evokes. Changes evoked by the actions of second messengers are usually rapid

Adenylate cyclase, cAMP and PKA

Amplification via 2nd messenger

Transmembrane kinase-linked receptorsCertain receptors have intrinsic kinase activity. These include receptors for growth factors, insulin etc. Receptors for growth factors usually have intrinsic tyrosine kinase activity Other tyrosine-kinase associated receptor, such as those for Growth Hormone, Prolactin and the cytokines, do not have intrinsic kinase activity, but activate soluble, intracellular kinases such as the Jak kinases. In addition, a newly described class of receptors have intrinsic serine/threonine kinase activitythis class includes receptors for inhibin, activin, TGFb, and Mullerian Inhibitory Factor (MIF).

Receptors for lipid-soluble hormones reside within the cellBecause these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell. The lipid soluble hormone diffuses into the cell and binds to the receptor which undergoes a conformational change. The receptor-hormone complex is then binds to specific DNA sequences called response elements. These DNA sequences are in the regulatory regions of genes.

Receptors for lipid-soluble hormones reside within the cellThe receptor-hormone complex binds to the regulatory region of the gene and changes the expression of that gene. In most cases binding of receptor-hormone complex to the gene stimulating the transcription of messenger RNA. The messenger RNA travels to the cytoplasm where it is translated into protein. The translated proteins that are produced participate in the response that is evoked by the hormone in the target cellResponses evoked by lipid soluble hormones are usually SLOW, requiring transcription/translation to evoke physiological responses.

Receptor control mechanismsHormonally induced negative regulation of receptors is referred to as homologous-desensitization This homeostatic mechanism protects from toxic effects of hormone excess. Heterologous desensitization occurs when exposure of the cell to one agonist reduces the responsiveness of the cell any other agonist that acts through a different receptor. This most commonly occurs through receptors that act through the adenylyl cyclase system. Heterologous desensitization results in a broad pattern of refractoriness with slower onset than homologous desensitization

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